Pyrimidinyl and 1,3,5-triazinyl benzimidazole sulfonamides and their use in cancer therapy

ABSTRACT

Provided herein are pyrimidinyl and 1,3,5-triazinyl benzimidazole sulfonamides, e.g., compounds of Formulae IA, IB, and IC, and their pharmaceutical compositions, preparation, and use as agents or drugs for cancer therapy, either alone or in combination with radiation and/or other anticancer drugs.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. §119(e) to U.S.Provisional Application No. 61/164,359, filed Mar. 27, 2009; 61/223,687,filed Jul. 7, 2009; and 61/247,454, filed Sep. 30, 2009; the disclosureof each of which is incorporated herein by reference in its entirety.

FIELD

Provided herein are pyrimidinyl and 1,3,5-triazinyl benzimidazolesulfonamides, and their pharmaceutical compositions, preparation, anduse as agents or drugs for cancer therapy, either alone or incombination with radiation and/or other anticancer drugs.

BACKGROUND

Phosphoinositide-3-kinases (PI3Ks) are a group of lipid kinases, whichphosphorylate the 3-hydroxyl of phosphoinositides. They are classifiedinto at least three classes (Classes I, II, and III) and play animportant role in cellular signaling (Stephens et al., Curr. Opin.Pharmacol. 2005, 5, 357). Class I enzymes are further classified intoClasses Ia and Ib based on their mechanism of activation; Class Ia PI3Ksare heterodimeric structures consisting of a catalytic subunit (p110α,p110β, or p110δ) in complex with a regulatory p85 subunit, while theclass-Ib PI3K (p110γ) is structurally similar but lacks the p85regulatory subunit, and instead is activated by βγ subunits ofheterotrimeric G-proteins (Walker et al., Mol. Cell. 2000, 6, 909). Thehuman protein sequence of the p110α isoform is described in Volina etal., Genomics 1994, 24, 472; and Stirdivant et al., Bioorg. Med. Chem.1997, 5, 65.

PI3Ks play a variety of roles in normal tissue physiology (Foukas &Shepherd, Biochem. Soc. Trans. 2004, 32, 330; Shepherd, Acta Physiol.Scand. 2005, 183, 3), with p110α having a specific role in cancergrowth, p110β in thrombus formation mediated by integrin α_(II)β₃(Jackson et al., Nat. Med. 2005, 11, 507), and p110γ in inflammation,rheumatoid arthritis (Camps et al., Nat. Med. 2005, 11, 936) and otherchronic inflammation states (Barber et al., Nat. Med. 2005, 11, 933).The PI3K enzymes produce phosphoinositide 3,4,5-triphosphate (PIP3) fromthe corresponding diphosphate (PIP2), thus recruiting AKT (proteinkinase B) through its Pleckstrin homology (PH) domain to the plasmamembrane. Once bound, AKT is phosphorylated and activated by othermembrane bound kinases and is central to a cascade of events that leadto inhibition of apoptosis (Berrie, Exp. Opin. Invest. Drugs 2001, 10,1085).

The p110α isoform is selectively amplified and activated in a number ofcancer types (Stephens et al., Curr. Opin. Pharmacol. 2005, 5, 357;Stauffer et al., Curr. Med. Chem.—Anti-Cancer Agents 2005, 5, 449). Inaddition, there is a high frequency of non-random mutations in specificsites, primarily in the C2 domain and or the activation loop, of thekinase in several human cancer cell lines, including colon, brain,breast, and stomach (Samuels et al., Science 2004, 304, 554). Thisresults in a constitutively active enzyme (Ikenoue et al., Cancer Res.2005, 65, 4562; Kang et al., Proc. Natl. Acad. Sci. USA 2005, 102, 802),making p110α one of the most highly mutated oncogenes found in humantumors. Structural studies have shown that many of the mutations occurat residues lying at the interfaces between p110α and p85α or betweenthe kinase domain of p110α and other domains within the catalyticsubunit (Miled et al., Science 2007, 317, 239; Huang et al., Science2007, 318, 1744).

While PI3K isoenzymes play important roles in many cellular processes,published experimental studies in mice with human tumor xenografts showthat the pan-PI3K inhibitor LY294002 is well-tolerated, reducessignaling through the PI3K pathway, causes reduction of tumor volume,and is more active in cell lines over-expressing mutant forms of p110αthan parental control cells (Semba et al., Clin. Cancer Res. 2002, 8,1957; Hu et al., Cancer Res. 2002, 62, 1087).

Thus, PI3K, especially the p110α isoform, is an interesting target fordrug intervention. Several classes of compounds have been identified asreversible inhibitors; for example, LY 294002 (non-selective) (Walker etal., Mol. Cell. 2000, 6, 909), PI103 (slightly α-selective) (Knight etal., Cell 2006, 125, 733; Hayakawa et al., Bioorg. Med. Chem. Lett.2007, 17, 2438; Raynaud et al., Cancer Res. 2007, 67, 5840), ZSTK474(non-selective) (Yaguchi et al., J. Natl. Cancer Inst. 2006, 98, 545;Kong et al., Cancer Sci. 2007, 98, 1639), TGX221 (β-selective) (Jacksonet al., Nat. Med. 2005, 11, 507), oxazines (γ-selective) (Lanni et al.,Bioorg. Med. Chem. Lett. 2007, 17, 756), IC87114 (δ-selective) (Sadhu etal. WO 2001/81346; Billottet et al., Oncogene 2006, 25, 6648), AS605240(γ-selective) (Camps et al., Nat. Med. 2005, 11, 936), theimidazo[1,2-a]pyridines (α-selective) (Hayakawa et al., Bioorg. Med.Chem. 2007, 15, 403; Hayakawa et al., Bioorg. Med. Chem. 2007, 15,5837), and the imidazo[4,5-c]quinoline NVP-BEZ235 (Garcia-Echeverria, etal., WO 2006/122806).

Despite the advances in developing PI3K inhibitors, there is a need forPI3K inhibitors for treatment of cancer.

SUMMARY OF THE DISCLOSURE

Provided herein is a compound of Formula IA, IB, or IC:

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof; or a pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof; wherein:

each R¹ and R² is independently (a) hydrogen, cyano, halo, or nitro; (b)C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl,C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a),—C(O)OR^(1b), —C(O)NR^(1b)R^(1c), —C(NR^(a))NR^(1b)R^(1c), —OR^(1a),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); wherein each R^(1a), R^(1b),R^(1c), and R^(1d) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl; or (iii) R^(1b) and R^(1c) together withthe N atom to which they are attached form heterocyclyl;

each R³ and R⁴ is independently hydrogen or C₁₋₆ alkyl; or R³ and R⁴ arelinked together to form a bond, C₁₋₆ alkylene, C₁₋₆ heteroalkylene, C₂₋₆alkenylene, or C₂₋₆ heteroalkenylene;

each R⁵ is independently C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, C₃₋₇ cycloalkyl-C₁₋₆ alkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, heteroaryl-C₁₋₆ alkyl, heterocyclyl, heterocyclyl-C₁₋₆alkyl, or —NR^(5m)R^(5n), where R^(5m) and R^(5n) are each independentlyhydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl;

each R⁶ is independently hydrogen or C₁₋₆ alkyl;

each A, B, D, and E is independently a bond, C, O, N, S, NR⁷, C(O), CR⁷,or CR⁷R^(7′), where each R⁷ and R^(7′) is independently hydrogen, halo,C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl; wherein the bonds between A,B, D, and E may be saturated or unsaturated; with the proviso that nomore than one of A, B, D, and E are a bond;

each Q is C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene, C₃₋₇cycloalkylene, C₆₋₁₄ arylene, heteroarylene, or heterocyclylene;

each T¹ is independently a bond, C₁₋₆ alkylene, —O—, or —NR⁸—;

each T² is independently a bond, C₁₋₆ alkylene, or —NR⁸—;

with the proviso that at least one of the two atoms that are directlyattached to the —SO₂— group is nitrogen;

each R⁸ is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆alkynyl; and

X, Y, and Z are each independently a nitrogen atom or CR⁹, with theproviso that at least two of X, Y, and Z are nitrogen atoms; where R⁹ ishydrogen or C₁₋₆ alkyl;

wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene,heteroalkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl,arylene, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene inR¹, R², R³, R⁴, R⁵, R⁶, R⁷, R^(7′), R⁸, R⁹, R^(1a), R^(1b), R^(1c),R^(1d), R^(5m), R^(5n), Q, T¹, and T², is optionally substituted withone or more groups, in one embodiment, one, two, three, or four groups,each independently selected from (a) cyano, halo, and nitro; (b) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, and heterocyclyl, each optionally substituted withone or more, in one embodiment, one, two, three, or four, substituentsQ¹; and (c) —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(c),—C(NR^(a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a), —OC(O)OR^(a),—OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a), —OS(O)₂R^(a),—OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c), —NR^(b)R^(c), —NR^(a)C(O)R^(d),—NR^(a)C(O)OR^(d), —NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c),—NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c),—NR^(a)S(O)₂NR^(b)R^(c), —SR^(a), —S(O)R^(a), —S(O)₂R^(a),—S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c), wherein each R^(a), R^(b),R^(c), and R^(d) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl, each optionally substituted with one ormore, in one embodiment, one, two, three, or four, substituents Q¹; or(iii) R^(b) and R^(c) together with the N atom to which they areattached form heterocyclyl, optionally substituted with one or more, inone embodiment, one, two, three, or four, substituents Q¹;

wherein each Q¹ is independently selected from the group consisting of(a) cyano, halo, and nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, andheterocyclyl; and (c) —C(O)R^(e), —C(O)OR^(e), —C(O)NR^(f)R^(g),—C(NR^(e))NR^(f)R^(g), —OR^(e), —OC(O)R^(e), —OC(O)OR^(e),—OC(O)NR^(f)R^(g), —OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e), —OS(O)₂R^(e),—OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g), —NR^(f)R^(g), —NR^(e)C(O)R^(h),—NR^(e)C(O)OR^(h), —NR^(e)C(O)NR^(f)R^(g), —NR^(e)C(═NR^(h))NR^(f)R^(g),—NR^(e)S(O)R^(h), —NR^(e)S(O)₂R^(h), —NR^(e)S(O)NR^(f)R^(g),—NR^(e)S(O)₂NR^(f)R^(g), —SR^(e), —S(O)R^(e), —S(O)₂R^(e),—S(O)NR^(f)R^(g), and —S(O)₂NR^(f)R^(g); wherein each R^(e), R^(f),R^(g), and R^(h) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl; or (iii) R^(f) and R^(g) together with theN atom to which they are attached form heterocyclyl.

Provided herein is a compound of Formula IA, IB, or IC:

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof; or a pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof;wherein:

each R¹ and R² is independently (a) hydrogen, cyano, halo, or nitro; (b)C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl,C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a),—C(O)OR^(1b), —C(O)NR^(1b)R^(1c), —C(NR^(a))NR^(1b)R^(1c), —OR^(1a),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); wherein each R^(1a), R^(1b),R^(1c), and R^(1d) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl; or (iii) R^(1b) and R^(1c) together withthe N atom to which they are attached form heterocyclyl;

each R³ and R⁴ is independently hydrogen or C₁₋₆ alkyl; or R³ and R⁴ arelinked together to form a bond, C₁₋₆ alkylene, C₁₋₆ heteroalkylene, C₂₋₆alkenylene, or C₂₋₆ heteroalkenylene;

each R⁵ is independently C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl;

each R⁶ is independently hydrogen or C₁₋₆ alkyl;

each A, B, D, and E is independently a bond, C, O, N, S, NR⁷, CR⁷, orCR⁷R^(7′), where each R⁷ and R^(7′) is independently hydrogen, halo,C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl; wherein the bonds between A,B, D, and E may be saturated or unsaturated; with the proviso that nomore than one of A, B, D, and E are a bond;

each Q is C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene, C₃₋₇cycloalkylene, C₆₋₁₄ arylene, heteroarylene, or heterocyclylene;

each T¹ is independently a bond, —O—, or —NR⁸—;

each T² is independently a bond or —NR⁸—, with the proviso that the atomthat is attached to —SO₂R⁵ is nitrogen;

each R⁸ is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆alkynyl; and

X, Y, and Z are each independently a nitrogen atom or CR⁹, with theproviso that at least two of X, Y, and Z are nitrogen atoms; where R⁹ ishydrogen or C₁₋₆ alkyl;

wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene,heteroalkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl,arylene, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene inR¹, R², R³, R⁴, R⁵, R⁶, R⁷, R^(7′), R⁸, R⁹, R^(1a), R^(1b), R^(1c),R^(1d), and Q is optionally substituted with one or more groups, in oneembodiment, one, two, three, or four groups, each independently selectedfrom (a) cyano, halo, and nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, andheterocyclyl, each optionally substituted with one or more, in oneembodiment, one, two, three, or four, substituents Q¹; and (c)—C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(c), —C(NR^(a))NR^(b)R^(c),—OR^(a), —OC(O)R^(a), —OC(O)OR^(a), —OC(O)NR^(b)R^(c),—OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a), —OS(O)₂R^(a), —OS(O)NR^(b)R^(c),—OS(O)₂NR^(b)R^(c), —NR^(b)R^(c), —NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d),—NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d),—NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c),—SR^(a), —S(O)R^(a), —S(O)₂R^(a), —S(O)NR^(b)R^(c), and—S(O)₂NR^(b)R^(e), wherein each R^(a), R^(b), R^(c), and R^(d) isindependently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl,each optionally substituted with one or more, in one embodiment, one,two, three, or four, substituents Q¹; or (iii) R^(b) and R^(c) togetherwith the N atom to which they are attached form heterocyclyl, optionallysubstituted with one or more, in one embodiment, one, two, three, orfour, substituents Q¹;

wherein each Q¹ is independently selected from the group consisting of(a) cyano, halo, and nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, andheterocyclyl; and (c) —C(O)R^(e), —C(O)OR^(e), —C(O)NR^(f)R^(g),—C(NR^(e))NR^(f)R^(g), —OR^(e), —OC(O)R^(e), —OC(O)OR^(e),—OC(O)NR^(f)R^(g), —OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e), —OS(O)₂R^(e),—OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g), —NR^(f)R^(g), —NR^(e)C(O)R^(h),—NR^(e)C(O)OR^(h), —NR^(e)C(O)NR^(f)R^(g), —NR^(e)C(═NR^(h))NR^(f)R^(g),—NR^(e)S(O)R^(h), —NR^(e)S(O)₂R^(h), —NR^(e)S(O)NR^(f)R^(g),—NR^(e)S(O)₂NR^(f)R^(g), —SR^(e), —S(O)R^(e), —S(O)₂R^(e),—S(O)NR^(f)R^(g), and —S(O)₂NR^(f)R^(g); wherein each R^(e), R^(f),R^(g), and R^(h) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl; or (iii) R^(f) and R^(g) together with theN atom to which they are attached form heterocyclyl.

Also provided herein is a compound of Formula IA, IB, or IC:

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof; or a pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof; wherein:

each R¹ and R² is independently (a) hydrogen, cyano, halo, or nitro; (b)C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl,C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a),—C(O)OR^(1b), —C(O)NR^(1b)R^(1c), —C(NR^(a))NR^(1b)R^(1c), —OR^(1a),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); wherein each R^(1a), R^(1b),R^(1c), and R^(1d) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl, each optionally substituted with one ormore, in one embodiment, one, two, three, or four, substituents Q¹; or(iii) R^(1b) and R^(1c) together with the N atom to which they areattached form heterocyclyl, optionally substituted with one or more, inone embodiment, one, two, three, or four, substituents Q¹;

each R³ and R⁴ is independently hydrogen or C₁₋₆ alkyl;

each R⁵ is independently C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl;

each R⁶ is independently hydrogen or C₁₋₆ alkyl;

each A, B, D, and E is independently (i) a bond; (ii) a nitrogen,oxygen, or sulfur atom; or (iii) CR⁷, where R⁷ is hydrogen, halo, C₁₋₆alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl; wherein the bonds between A, B, D,and E may be saturated or unsaturated; with the proviso that no morethan one of A, B, D, and E are a bond;

each Q is C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene, C₃₋₇cycloalkylene, C₆₋₁₄ arylene, heteroarylene, or heterocyclylene;

each T¹ is independently a bond, —O—, or —NR⁸—;

each T² is independently a bond or —NR⁸—, with the proviso that the atomthat is attached to —SO₂R⁵ is nitrogen;

each R⁸ is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆alkynyl; and

X, Y, and Z are each independently a nitrogen atom or CR⁹, with theproviso that at least two of X, Y, and Z are nitrogen atoms; where R⁹ ishydrogen or C₁₋₆ alkyl;

wherein each alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene,cycloalkyl, cycloalkylene, aryl, arylene, heteroaryl, heteroarylene,heterocyclyl, and heterocyclylene is optionally substituted with one ormore groups, each independently selected from (a) cyano, halo, andnitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, and heterocyclyl, each optionallysubstituted with one or more, in one embodiment, one, two, three, orfour, substituents Q¹; and (c) —C(O)R^(a), —C(O)OR^(a),—C(O)NR^(b)R^(c), —C(NR^(a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a),—OC(O)OR^(a), —OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a),—OS(O)₂R^(a), —OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c), —NR^(b)R^(c),—NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d), —NR^(a)C(O)NR^(b)R^(c),—NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d),—NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c), —SR^(a), —S(O)R^(a),—S(O)₂R^(a), —S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c), wherein eachR^(a), R^(b), R^(c), and R^(d) is independently (i) hydrogen; (ii) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl, each optionally substituted withone or more, in one embodiment, one, two, three, or four, substituentsQ¹; or (iii) R^(b) and R^(c) together with the N atom to which they areattached form heterocyclyl, optionally substituted with one or more, inone embodiment, one, two, three, or four, substituents Q¹;

wherein each Q¹ is independently selected from the group consisting of(a) cyano, halo, and nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, andheterocyclyl; and (c) —C(O)R^(e), —C(O)OR^(e), —C(O)NR^(f)R^(g),—C(NR^(e))NR^(f)R^(g), —OR^(e), —OC(O)R^(e), —OC(O)OR^(e),—OC(O)NR^(f)R^(g), —OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e), —OS(O)₂R^(e),—OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g), —NR^(f)R^(g), —NR^(e)C(O)R^(h),—NR^(e)C(O)OR^(h), —NR^(e)C(O)NR^(f)R^(g), —NR^(e)C(═NR^(h))NR^(f)R^(g),—NR^(e)S(O)R^(h), —NR^(e)S(O)₂R^(h), —NR^(e)S(O)NR^(f)R^(g),—NR^(e)S(O)₂NR^(f)R^(g), —SR^(e), —S(O)R^(e), —S(O)₂R^(e),—S(O)NR^(f)R^(g), and —S(O)₂NR^(f)R^(g); wherein each R^(e), R^(f),R^(g), and R^(h) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl; or (iii) R^(f) and R^(g) together with theN atom to which they are attached form heterocyclyl.

Additionally provided herein is a compound of Formula Ia, Ib, or Ic:

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof; or a pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof; wherein:

each R¹ and R² is independently (a) hydrogen, cyano, halo, or nitro; (b)C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl,C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a),—C(O)OR^(1b), —C(O)NR^(1b)R^(1c), —C(NR^(a))NR^(1b)R^(1c), —OR^(1a),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); wherein each R^(1a), R^(1b),R^(1c), and R^(1d) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl, each optionally substituted with one ormore, in one embodiment, one, two, three, or four, substituents Q¹; or(iii) R^(1b) and R^(1c) together with the N atom to which they areattached form heterocyclyl, optionally substituted with one or more, inone embodiment, one, two, three, or four, substituents Q¹;

each R³ and R⁴ is independently hydrogen or C₁₋₆ alkyl;

each R⁵ is independently C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl;

each R⁶ is independently hydrogen or C₁₋₆ alkyl;

each A, B, D, and E is independently (i) a bond; (ii) a nitrogen,oxygen, or sulfur atom; or (iii) CR⁷, where R⁷ is hydrogen, halo, C₁₋₆alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl; wherein the bonds between A, B, D,and E may be saturated or unsaturated; with the proviso that no morethan one of A, B, D, and E are a bond;

each Q is C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene, C₃₋₇cycloalkylene, C₆₋₁₄ arylene, heteroarylene, or heterocyclylene;

each T¹ is independently a bond, —O—, or —NR⁸—;

each T² is independently a bond or —NR⁸—, with the proviso that the atomthat is attached to —SO₂R⁵ is nitrogen;

each R⁸ is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆alkynyl; and

X, Y, and Z are each independently a nitrogen atom or CR⁹, with theproviso that at least two of X, Y, and Z are nitrogen atoms; where R⁹ ishydrogen or C₁₋₆ alkyl;

wherein each alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene,cycloalkyl, cycloalkylene, aryl, arylene, heteroaryl, heteroarylene,heterocyclyl, and heterocyclylene is optionally substituted with one ormore groups, each independently selected from (a) cyano, halo, andnitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, and heterocyclyl, each optionallysubstituted with one or more, in one embodiment, one, two, three, orfour, substituents Q¹; and (c) —C(O)R^(a), —C(O)OR^(a),—C(O)NR^(b)R^(c), —C(NR^(a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a),—OC(O)OR^(a), —OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a),—OS(O)₂R^(a), —OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c), —NR^(b)R^(c),—NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d), —NR^(a)C(O)NR^(b)R^(c),—NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d),—NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c), —SR^(a), —S(O)R^(a),—S(O)₂R^(a), —S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c), wherein eachR^(a), R^(b), R^(c), and R^(d) is independently (i) hydrogen; (ii) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl, each optionally substituted withone or more, in one embodiment, one, two, three, or four, substituentsQ¹; or (iii) R^(b) and R^(c) together with the N atom to which they areattached form heterocyclyl, optionally substituted with one or more, inone embodiment, one, two, three, or four, substituents Q¹;

wherein each Q¹ is independently selected from the group consisting of(a) cyano, halo, and nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, andheterocyclyl; and (c) —C(O)R^(e), —C(O)OR^(e), —C(O)NR^(f)R^(g),—C(NR^(e))NR^(f)R^(g), —OR^(e), —OC(O)R^(e), —OC(O)OR^(e),—OC(O)NR^(f)R^(g), —OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e), —OS(O)₂R^(e),—OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g), —NR^(f)R^(g), —NR^(e)C(O)R^(h),—NR^(e)C(O)OR^(h), —NR^(e)C(O)NR^(f)R^(g), —NR^(e)C(═NR^(h))NR^(f)R^(g),—NR^(e)S(O)R^(h), —NR^(e)S(O)₂R^(h), —NR^(e)S(O)NR^(f)R^(g),—NR^(e)S(O)₂NR^(f)R^(g), —SR^(e), —S(O)R^(e), —S(O)₂R^(e),—S(O)NR^(f)R^(g), and —S(O)₂NR^(f)R^(g); wherein each R^(e), R^(f),R^(g), and R^(h) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl; or (iii) R^(f) and R^(g) together with theN atom to which they are attached form heterocyclyl.

Provided herein are pharmaceutical compositions comprising a compounddisclosed herein, e.g., a compound of Formula IA, IB, or IC, includingan enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers; or a pharmaceutically acceptable salt, solvate, hydrate,or prodrug thereof; in combination with one or more pharmaceuticallyacceptable carriers.

Provided herein is a method for treating, preventing, or amelioratingone or more symptoms of a PI3K-mediated disorder, disease, or conditionin a subject, comprising administering to the subject a therapeuticallyeffective amount of a compound disclosed herein, e.g., a compound ofFormula IA, IB, or IC, an enantiomer, a mixture of enantiomers, amixture of two or more diastereomers; or a pharmaceutically acceptablesalt, solvate, hydrate, or prodrug thereof.

Provided herein is a method for modulating PI3K activity, comprisingcontacting a PI3K with a therapeutically effective amount of a compounddisclosed herein, e.g., a compound of Formula IA, IB, or IC, includingan enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers; or a pharmaceutically acceptable salt, solvate, hydrate,or prodrug thereof.

DETAILED DESCRIPTION

To facilitate understanding of the disclosure set forth herein, a numberof terms are defined below.

Generally, the nomenclature used herein and the laboratory procedures inorganic chemistry, medicinal chemistry, and pharmacology describedherein are those well known and commonly employed in the art. Unlessdefined otherwise, all technical and scientific terms used hereingenerally have the same meaning as commonly understood by one ofordinary skill in the art to which this disclosure belongs.

The term “subject” refers to an animal, including, but not limited to, aprimate (e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit,rat, or mouse. The terms “subject” and “patient” are usedinterchangeably herein in reference, for example, to a mammaliansubject, such as a human subject, in one embodiment, a human.

The terms “treat,” “treating,” and “treatment” are meant to includealleviating or abrogating a disorder, disease, or condition, or one ormore of the symptoms associated with the disorder, disease, orcondition; or alleviating or eradicating the cause(s) of the disorder,disease, or condition itself.

The terms “prevent,” “preventing,” and “prevention” are meant to includea method of delaying and/or precluding the onset of a disorder, disease,or condition, and/or its attendant symptoms; barring a subject fromacquiring a disorder, disease, or condition; or reducing a subject'srisk of acquiring a disorder, disease, or condition.

The term “therapeutically effective amount” are meant to include theamount of a compound that, when administered, is sufficient to preventdevelopment of, or alleviate to some extent, one or more of the symptomsof the disorder, disease, or condition being treated. The term“therapeutically effective amount” also refers to the amount of acompound that is sufficient to elicit the biological or medical responseof a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell,tissue, system, animal, or human, which is being sought by a researcher,veterinarian, medical doctor, or clinician.

The term “pharmaceutically acceptable carrier,” “pharmaceuticallyacceptable excipient,” “physiologically acceptable carrier,” or“physiologically acceptable excipient” refers to apharmaceutically-acceptable material, composition, or vehicle, such as aliquid or solid filler, diluent, solvent, or encapsulating material. Inone embodiment, each component is “pharmaceutically acceptable” in thesense of being compatible with the other ingredients of a pharmaceuticalformulation, and suitable for use in contact with the tissue or organ ofhumans and animals without excessive toxicity, irritation, allergicresponse, immunogenicity, or other problems or complications,commensurate with a reasonable benefit/risk ratio. See, Remington: TheScience and Practice of Pharmacy, 21st Edition, Lippincott Williams &Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients,5th Edition, Rowe et al., Eds., The Pharmaceutical Press and theAmerican Pharmaceutical Association: 2005; and Handbook ofPharmaceutical Additives, 3rd Edition, Ash and Ash Eds., GowerPublishing Company: 2007; Pharmaceutical Preformulation and Formulation,2nd Edition, Gibson Ed., CRC Press LLC: Boca Raton, Fla., 2009.

The term “about” or “approximately” means an acceptable error for aparticular value as determined by one of ordinary skill in the art,which depends in part on how the value is measured or determined. Incertain embodiments, the term “about” or “approximately” means within 1,2, 3, or 4 standard deviations. In certain embodiments, the term “about”or “approximately” means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%,4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

The terms “active ingredient” and “active substance” refer to acompound, which is administered, alone or in combination with one ormore pharmaceutically acceptable excipients, to a subject for treating,preventing, or ameliorating one or more symptoms of a condition,disorder, or disease. As used herein, “active ingredient” and “activesubstance” may be an optically active isomer of a compound describedherein.

The terms “drug,” “therapeutic agent,” and “chemotherapeutic agent”refer to a compound, or a pharmaceutical composition thereof, which isadministered to a subject for treating, preventing, or ameliorating oneor more symptoms of a condition, disorder, or disease.

The term “PI3K” refers to a phosphoinositide 3-kinase or mutant thereof,which is capable of phosphorylating the inositol ring of PI in the D-3position. The term “PI3K mutant” is intended to include proteinssubstantially homologous to a native PI3K, i.e., proteins having one ormore naturally or non-naturally occurring amino acid deletions,insertions, or substitutions (e.g., PI3K derivatives, homologs, andfragments), as compared to the amino acid sequence of a native PI3K. Theamino acid sequence of a PI3K mutant is at least about 80% identical, atleast about 90% identical, or at least about 95% identical to a nativePI3K. Examples of PI3K include, but are not limited to, p110α, p110β,p110δ, p110γ, PI3K-C2α, PI3K-C2β, PI3K-C2γ, Vps34, mTOR, ATM, ATR, andDNA-PK. See, Fry, Biochem. Biophys. Acta 1994, 1226, 237-268;Vanhaesebroeck and Waterfield, Exp. Cell. Res. 1999, 253, 239-254; andFry, Breast Cancer Res. 2001, 3, 304-312. PI3Ks are classified into atleast three classes. Class I includes p110α, p110β, p110δ, and p110γ.Class II includes PI3K-C2α, PI3K-C2β, and PI3K-C2γ. Class III includesVps34. Class IV includes mTOR, ATM, ATR, and DNA-PK. In certainembodiments, the PI3K is a Class I kinase. In certain embodiments, thePI3K is p110α, p110β, p110δ, or p110γ. In certain embodiments, the PI3Kis a mutant of a Class I kinase. In certain embodiments, the PI3K is ap110α mutant. Examples of p110α mutants include, but are not limited to,R38H, G106V, K111N, K227E, N345K, C420R, P539R, E542K, E545A, E545G,E545K, Q546K, Q546P, E453Q, H710P, I800L, T1025S, M1043I, M1043V,H1047L, H1047R, and H1047Y (Ikenoue et al., Cancer Res. 2005, 65,4562-4567; Gymnopoulos et al., Proc. Natl. Acad. Sci., 2007, 104,5569-5574). In certain embodiments, the PI3K is a Class II kinase. Incertain embodiments, the PI3K is PI3K-C2α, PI3K-C2β, or PI3K-C2γ. Incertain embodiments, the PI3K is a Class III kinase. In certainembodiments, the PI3K is Vps34. In certain embodiments, the PI3K is aClass IV kinase. In certain embodiments, the PI3K is mTOR, ATM, ATR, orDNA-PK.

The terms “PI3K-mediated disorder or disease” and “a condition, disorderor disease mediated by PI3K” refer to a condition, disorder, or diseasecharacterized by inappropriate, e.g., less than or greater than normal,PI3K activity. Inappropriate PI3K functional activity might arise as theresult of PI3K expression in cells which normally do not express PI3K,increased PI3K expression or degree of intracellular activation; ordecreased PI3K expression. A PI3K-mediated condition, disorder ordisease may be completely or partially mediated by inappropriate PI3Kactivity. In particular, a PI3K-mediated condition, disorder or diseaseis one in which modulation of a PI3K enzyme activity results in someeffect on the underlying condition or disorder, e.g., a PI3K inhibitorresults in some improvement in at least some of patients being treated.

The term “alkyl” refers to a linear or branched saturated monovalenthydrocarbon radical, wherein the alkylene may optionally be substitutedas described herein. The term “alkyl” also encompasses both linear andbranched alkyl, unless otherwise specified. In certain embodiments, thealkyl is a linear saturated monovalent hydrocarbon radical that has 1 to20 (C₁₋₂₀), 1 to 15 (C₁₋₁₅), 1 to 10 (C₁₋₁₀), or 1 to 6 (C₁₋₆) carbonatoms, or branched saturated monovalent hydrocarbon radical of 3 to 20(C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to 10 (C₃₋₁₀), or 3 to 6 (C₃₋₆) carbonatoms. As used herein, linear C₁₋₆ and branched C₃₋₆ alkyl groups arealso referred as “lower alkyl.” Examples of alkyl groups include, butare not limited to, methyl, ethyl, propyl (including all isomericforms), n-propyl, isopropyl, butyl (including all isomeric forms),n-butyl, isobutyl, sec-butyl, t-butyl, pentyl (including all isomericforms), and hexyl (including all isomeric forms). For example, C₁₋₆alkyl refers to a linear saturated monovalent hydrocarbon radical of 1to 6 carbon atoms or a branched saturated monovalent hydrocarbon radicalof 3 to 6 carbon atoms.

The term “alkylene” refers to a linear or branched saturated divalenthydrocarbon radical, wherein the alkylene may optionally be substitutedas described herein. The term “alkylene” encompasses both linear andbranched alkylene, unless otherwise specified. In certain embodiments,the alkylene is a linear saturated divalent hydrocarbon radical that has1 to 20 (C₁₋₂₀), 1 to 15 (C₁₋₁₅), 1 to 10 (C₁₋₁₀), or 1 to 6 (C₁₋₆)carbon atoms, or branched saturated divalent hydrocarbon radical of 3 to20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to 10 (C₃₋₁₀), or 3 to 6 (C₃₋₆) carbonatoms. As used herein, linear C₁₋₆ and branched C₃₋₆ alkylene groups arealso referred as “lower alkylene.” Examples of alkylene groups include,but are not limited to, methylene, ethylene, propylene (including allisomeric forms), n-propylene, isopropylene, butylene (including allisomeric forms), n-butylene, isobutylene, t-butylene, pentylene(including all isomeric forms), and hexylene (including all isomericforms). For example, C₁₋₆ alkylene refers to a linear saturated divalenthydrocarbon radical of 1 to 6 carbon atoms or a branched saturateddivalent hydrocarbon radical of 3 to 6 carbon atoms.

The term “heteroalkylene” refers to a linear or branched saturateddivalent hydrocarbon radical that contains one or more heteroatoms eachindependently selected from O, S, and N in the hydrocarbon chain. Forexample, C₁₋₆ heteroalkylene refers to a linear saturated divalenthydrocarbon radical of 1 to 6 carbon atoms or a branched saturateddivalent hydrocarbon radical of 3 to 6 carbon atoms. In certainembodiments, the heteroalkylene is a linear saturated divalenthydrocarbon radical that has 1 to 20 (C₁₋₂₀), 1 to 15 (C₁₋₁₅), 1 to 10(C₁₋₁₀), or 1 to 6 (C₁₋₆) carbon atoms, or branched saturated divalenthydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to 10(C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. As used herein, linear C₁₋₆ andbranched C₃₋₆ heteroalkylene groups are also referred as “lowerheteroalkylene.” Examples of heteroalkylene groups include, but are notlimited to, —CH₂O—, —CH₂OCH₂—, —CH₂CH₂O—, —CH₂NH—, —CH₂NHCH₂—,—CH₂CH₂NH—, —CH₂S—, —CH₂SCH₂—, and —CH₂CH₂S—. In certain embodiments,heteroalkylene may also be optionally substituted as described herein.

The term “alkenyl” refers to a linear or branched monovalent hydrocarbonradical, which contains one or more, in one embodiment, one to five,carbon-carbon double bonds. The alkenyl may be optionally substituted asdescribed herein. The term “alkenyl” also embraces radicals having “cis”and “trans” configurations, or alternatively, “Z” and “E”configurations, as appreciated by those of ordinary skill in the art. Asused herein, the term “alkenyl” encompasses both linear and branchedalkenyl, unless otherwise specified. For example, C₂₋₆ alkenyl refers toa linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbonatoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6carbon atoms. In certain embodiments, the alkenyl is a linear monovalenthydrocarbon radical of 2 to 20 (C₂₋₂₀), 2 to 15 (C₂₋₁₅), 2 to 10(C₂₋₁₀), or 2 to 6 (C₂₋₆) carbon atoms, or a branched monovalenthydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to 10(C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. Examples of alkenyl groupsinclude, but are not limited to, ethenyl, propen-1-yl, propen-2-yl,allyl, butenyl, and 4-methylbutenyl.

The term “alkenylene” refers to a linear or branched divalenthydrocarbon radical, which contains one or more, in one embodiment, oneto five, carbon-carbon double bonds. The alkenylene may be optionallysubstituted as described herein. Similarly, the term “alkenylene” alsoembraces radicals having “cis” and “trans” configurations, oralternatively, “E” and “Z” configurations. As used herein, the term“alkenylene” encompasses both linear and branched alkenylene, unlessotherwise specified. For example, C₂₋₆ alkenylene refers to a linearunsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or abranched unsaturated divalent hydrocarbon radical of 3 to 6 carbonatoms. In certain embodiments, the alkenylene is a linear divalenthydrocarbon radical of 2 to 20 (C₂₋₂₀), 2 to 15 (C₂₋₁₅), 2 to 10(C₂₋₁₀), or 2 to 6 (C₂₋₆) carbon atoms, or a branched divalenthydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to 10(C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. Examples of alkenylene groupsinclude, but are not limited to, ethenylene, allylene, propenylene,butenylene, and 4-methylbutenylene.

The term “heteroalkenylene” refers to a linear or branched divalenthydrocarbon radical, which contains one or more, in one embodiment, oneto five, in another embodiment, one, carbon-carbon double bond(s), andwhich contains one or more heteroatoms each independently selected fromO, S, and N in the hydrocarbon chain. The heteroalkenylene may beoptionally substituted as described herein. The term “heteroalkenylene”embraces radicals having a “cis” or “trans” configuration or a mixturethereof, or alternatively, a “Z” or “E” configuration or a mixturethereof, as appreciated by those of ordinary skill in the art. Forexample, C₂₋₆ heteroalkenylene refers to a linear unsaturated divalenthydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturateddivalent hydrocarbon radical of 3 to 6 carbon atoms. In certainembodiments, the heteroalkenylene is a linear divalent hydrocarbonradical of 2 to 20 (C₂₋₂₀), 2 to 15 (C₂₋₁₅), 2 to 10 (C₂₋₁₀), or 2 to 6(C₂₋₆) carbon atoms, or a branched divalent hydrocarbon radical of 3 to20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to 10 (C₃₋₁₀), or 3 to 6 (C₃₋₆) carbonatoms. Examples of heteroalkenylene groups include, but are not limitedto, —CH═CHO—, —CH═CHOCH₂—, —CH═CHCH₂O—, —CH═CHS—, —CH═CHSCH₂—,—CH═CHCH₂S—, or —CH═CHCH₂NH—.

The term “alkynyl” refers to a linear or branched monovalent hydrocarbonradical, which contains one or more, in one embodiment, one to five,carbon-carbon triple bonds. The alkynyl may be optionally substituted asdescribed herein. The term “alkynyl” also encompasses both linear andbranched alkynyl, unless otherwise specified. In certain embodiments,the alkynyl is a linear monovalent hydrocarbon radical of 2 to 20(C₂₋₂₀), 2 to 15 (C₂₋₁₅), 2 to 10 (C₂₋₁₀), or 2 to 6 (C₂₋₆) carbonatoms, or a branched monovalent hydrocarbon radical of 3 to 20 (C₃₋₂₀),3 to 15 (C₃₋₁₅), 3 to 10 (C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms.Examples of alkynyl groups include, but are not limited to, ethynyl(—C≡CH) and propargyl (—CH₂C≡CH). For example, C₂₋₆ alkynyl refers to alinear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atomsor a branched unsaturated monovalent hydrocarbon radical of 3 to 6carbon atoms.

The term “alkynylene” refers to a linear or branched divalenthydrocarbon radical, which contains one or more, in one embodiment, oneto five, carbon-carbon triple bonds. The alkynylene may be optionallysubstituted as described herein. The term “alkynylene” also encompassesboth linear and branched alkynylene, unless otherwise specified. Incertain embodiments, the alkynylene is a linear divalent hydrocarbonradical of 2 to 20 (C₂₋₂₀), 2 to 15 (C₂₋₁₅), 2 to 10 (C₂₋₁₀), or 2 to 6(C₂₋₆) carbon atoms, or a branched divalent hydrocarbon radical of 3 to20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to 10 (C₃₋₁₀), or 3 to 6 (C₃₋₆) carbonatoms. Examples of alkynylene groups include, but are not limited to,ethynylene (—C≡C—) and propargylene (—CH₂C≡C—). For example, C₂₋₆alkynylene refers to a linear unsaturated divalent hydrocarbon radicalof 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbonradical of 3 to 6 carbon atoms.

The term “cycloalkyl” refers to a cyclic saturated bridged and/ornon-bridged monovalent hydrocarbon radical, which may be optionallysubstituted as described herein. In certain embodiments, the cycloalkylhas from 3 to 20 (C₃₋₂₀), from 3 to 15 (C₃₋₁₅), from 3 to 10 (C₃₋₁₀), orfrom 3 to 7 (C₃₋₇) carbon atoms. Examples of cycloalkyl groups include,but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl,decalinyl, and adamantyl.

The term “cycloalkylene” refers to a cyclic saturated bridged and/ornon-bridged divalent hydrocarbon radical, which may be optionallysubstituted as described herein. In certain embodiments, thecycloalkylene has from 3 to 20 (C₃₋₂₀), from 3 to 15 (C₃₋₁₅), from 3 to10 (C₃₋₁₀), or from 3 to 7 (C₃₋₇) carbon atoms. Examples ofcycloalkylene groups include, but are not limited to, cyclopropylene(e.g., 1,1-cyclopropylene and 1,2-cyclopropylene), cyclobutylene (e.g.,1,1-cyclobutylene, 1,2-cyclobutylene, or 1,3-cyclobutylene),cyclopentylene (e.g., 1,1-cyclopentylene, 1,2-cyclopentylene, or1,3-cyclopentylene), cyclohexylene (e.g., 1,1-cyclohexylene,1,2-cyclohexylene, 1,3-cyclohexylene, or 1,4-cyclohexylene),cycloheptylene (e.g., 1,1-cycloheptylene, 1,2-cycloheptylene,1,3-cycloheptylene, or 1,4-cycloheptylene), decalinylene, andadamantylene.

The term “aryl” refers to a monocyclic aromatic group and/or multicyclicmonovalent aromatic group that contain at least one aromatic hydrocarbonring. In certain embodiments, the aryl has from 6 to 20 (C₆₋₂₀), from 6to 15 (C₆₋₁₅), or from 6 to 10 (C₆₋₁₀) ring atoms. Examples of arylgroups include, but are not limited to, phenyl, naphthyl, fluorenyl,azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl. Arylalso refers to bicyclic or tricyclic carbon rings, where one of therings is aromatic and the others of which may be saturated, partiallyunsaturated, or aromatic, for example, dihydronaphthyl, indenyl,indanyl, or tetrahydronaphthyl (tetralinyl). In certain embodiments,aryl may be optionally substituted as described herein.

The term “arylene” refers to a monocyclic and/or multicyclic divalentaromatic group that contain at least one aromatic hydrocarbon ring. Incertain embodiments, the arylene has from 6 to 20 (C₆₋₂₀), from 6 to 15(C₆₋₁₅), or from 6 to 10 (C₆₋₁₀) ring atoms. Examples of arylene groupsinclude, but are not limited to, phenylene, naphthylene, fluorenylene,azulenylene, anthrylene, phenanthrylene, pyrenylene, biphenylene, andterphenylene. Arylene also refers to bicyclic or tricyclic carbon rings,where one of the rings is aromatic and the others of which may besaturated, partially unsaturated, or aromatic, for example,dihydronaphthylene, indenylene, indanylene, ortetrahydro-naphthylene(tetralinyl). In certain embodiments, arylene mayalso be optionally substituted as described herein.

The term “aralkyl” or “aryl-alkyl” refers to a monovalent alkyl groupsubstituted with aryl. In certain embodiments, the alkyl and arylmoieties are optionally substituted as described herein.

The term “heteroaryl” refers to a monocyclic aromatic group and/ormulticyclic aromatic group that contain at least one aromatic ring,wherein at least one aromatic ring contains one or more heteroatomsindependently selected from O, S, and N. Each ring of a heteroaryl groupcan contain one or two O atoms, one or two S atoms, and/or one to four Natoms, provided that the total number of heteroatoms in each ring isfour or less and each ring contains at least one carbon atom. In certainembodiments, the heteroaryl has from 5 to 20, from 5 to 15, or from 5 to10 ring atoms. Examples of monocyclic heteroaryl groups include, but arenot limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl,oxadiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl,tetrazolyl, triazinyl, and triazolyl. Examples of bicyclic heteroarylgroups include, but are not limited to, benzofuranyl, benzimidazolyl,benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl,benzothienyl, benzothiophenyl, benzotriazolyl, benzoxazolyl,furopyridyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl,indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl,isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl,pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl,quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl, and thienopyridyl.Examples of tricyclic heteroaryl groups include, but are not limited to,acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl,phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl,phenothiazinyl, phenoxazinyl, and xanthenyl. In certain embodiments,heteroaryl may also be optionally substituted as described herein.

The term “heteroarylene” refers to a divalent aromatic group and/ormulticyclic aromatic group that contain at least one aromatic ring,wherein at least one aromatic ring contains one or more heteroatomsindependently selected from O, S, and N. Each ring of a heteroarylenegroup can contain one or two O atoms, one or two S atoms, and/or one tofour N atoms, provided that the total number of heteroatoms in each ringis four or less and each ring contains at least one carbon atom. Incertain embodiments, the heteroarylene has from 5 to 20, from 5 to 15,or from 5 to 10 ring atoms. Examples of monocyclic heteroarylene groupsinclude, but are not limited to, furanylene, imidazolylene,isothiazolylene, isoxazolylene, oxadiazolylene, oxadiazolylene,oxazolylene, pyrazinylene, pyrazolylene, pyridazinylene, pyridylene,pyrimidinylene, pyrrolylene, thiadiazolylene, thiazolylene, thienylene,tetrazolylene, triazinylene, and triazolylene. Examples of bicyclicheteroarylene groups include, but are not limited to, benzofuranylene,benzimidazolylene, benzoisoxazolylene, benzopyranylene,benzothiadiazolylene, benzothiazolylene, benzothienylene,benzothiophenylene, benzotriazolylene, benzoxazolylene, furopyridylene,imidazopyridinylene, imidazothiazolylene, indolizinylene, indolylene,indazolylene, isobenzofuranylene, isobenzothienylene, isoindolylene,isoquinolinylene, isothiazolylene, naphthyridinylene,oxazolopyridinylene, phthalazinylene, pteridinylene, purinylene,pyridopyridylene, pyrrolopyridylene, quinolinylene, quinoxalinylene,quinazolinylene, thiadiazolopyrimidylene, and thienopyridylene. Examplesof tricyclic heteroaryl groups include, but are not limited to,acridinylene, benzindolylene, carbazolylene, dibenzofuranylene,perimidinylene, phenanthrolinylene, phenanthridinylene,phenarsazinylene, phenazinylene, phenothiazinylene, phenoxazinylene, andxanthenylene. In certain embodiments, heteroaryl may also be optionallysubstituted as described herein.

The term “heterocyclyl” or “heterocyclic” refers to a monocyclicnon-aromatic ring system and/or multicyclic ring system that contains atleast one non-aromatic ring, wherein one or more of the non-aromaticring atoms are heteroatoms independently selected from O, S, or N; andthe remaining ring atoms are carbon atoms. In certain embodiments, theheterocyclyl or heterocyclic group has from 3 to 20, from 3 to 15, from3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms. In certainembodiments, the heterocyclyl is a monocyclic, bicyclic, tricyclic, ortetracyclic ring system, which may include a fused or bridged ringsystem, and in which the nitrogen or sulfur atoms may be optionallyoxidized, the nitrogen atoms may be optionally quaternized, and somerings may be partially or fully saturated, or aromatic. The heterocyclylmay be attached to the main structure at any heteroatom or carbon atomwhich results in the creation of a stable compound. Examples of suchheterocyclic radicals include, but are not limited to, azepinyl,benzodioxanyl, benzodioxolyl, benzofuranonyl, benzopyranonyl,benzopyranyl, benzotetrahydrofuranyl, benzotetrahydrothienyl,benzothiopyranyl, benzoxazinyl, β-carbolinyl, chromanyl, chromonyl,cinnolinyl, coumarinyl, decahydroisoquinolinyl, dihydrobenzisothiazinyl,dihydrobenzisoxazinyl, dihydrofuryl, dihydroisoindolyl, dihydropyranyl,dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1,4-dithianyl,furanonyl, imidazolidinyl, imidazolinyl, indolinyl,isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl,isocoumarinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl,morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl,oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl,pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl,tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl,tetrahydrothienyl, thiamorpholinyl, thiazolidinyl, tetrahydroquinolinyl,and 1,3,5-trithianyl. In certain embodiments, heterocyclic may also beoptionally substituted as described herein.

The term “heterocyclylene” refers to a divalent non-aromatic ring systemand/or multicyclic ring system that contain at least one non-aromaticring, wherein one or more of the non-aromatic ring atoms are heteroatomsindependently selected from O, S, or N; and the remaining ring atoms arecarbon atoms. In certain embodiments, the heterocyclylene group has from3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5to 6 ring atoms. In certain embodiments, the heterocyclylene is amonocyclic, bicyclic, tricyclic, or tetracyclic ring system, which mayinclude a fused or bridged ring system, and in which the nitrogen orsulfur atoms may be optionally oxidized, the nitrogen atoms may beoptionally quaternized, and some rings may be partially or fullysaturated, or aromatic. The heterocyclylene may be attached to the mainstructure at any heteroatom or carbon atom which results in the creationof a stable compound. Examples of such heterocyclene groups include, butare not limited to, azepinylene, benzodioxanylene, benzodioxolylene,benzofuranonylene, benzopyranonylene, benzopyranylene,benzotetrahydrofuranylene, benzotetrahydrothienylene,benzothiopyranylene, benzoxazinylene, β-carbolinylene, chromanylene,chromonylene, cinnolinylene, coumarinylene, decahydroisoquinolinylene,dihydrobenzisothiazinylene, dihydrobenzisoxazinylene, dihydrofurylene,dihydroisoindolylene, dihydropyranylene, dihydropyrazolylene,dihydropyrazinylene, dihydropyridinylene, dihydropyrimidinylene,dihydropyrrolylene, dioxolanylene, 1,4-dithianylene, furanonylene,imidazolidinylene, imidazolinylene, indolinylene,isobenzotetrahydrofuranylene, isobenzotetrahydrothienylene,isochromanylene, isocoumarinylene, isoindolinylene, isothiazolidinylene,isoxazolidinylene, morpholinylene, octahydroindolylene,octahydroisoindolylene, oxazolidinonylene, oxazolidinylene, oxiranylene,piperazinylene, piperidinylene, 4-piperidonylene, pyrazolidinylene,pyrazolinylene, pyrrolidinylene, pyrrolinylene, quinuclidinylene,tetrahydrofurylene, tetrahydroisoquinolinylene, tetrahydropyranylene,tetrahydrothienylene, thiamorpholinylene, thiazolidinylene,tetrahydroquinolinylene, and 1,3,5-trithianylene. In certainembodiments, heterocyclic may also be optionally substituted asdescribed herein.

The term “halogen”, “halide” or “halo” refers to fluorine, chlorine,bromine, and/or iodine.

The term “optionally substituted” is intended to mean that a group, suchas an alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene,cycloalkyl, cycloalkylene, aryl, arylene, heteroaryl, heteroarylene,heterocyclyl, or heterocyclylene group, may be substituted with one ormore substituents independently selected from, e.g., (a) C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, and heterocyclyl, each optionally substituted with one ormore, in one embodiment, one, two, three, or four, substituents Q¹; and(b) halo, cyano (—CN), nitro (—NO₂), —C(O)R^(a), —C(O)OR^(a),—C(O)NR^(b)R^(c), —C(NR^(a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a),—OC(O)OR^(a), —OC(O)NR^(b)R^(c), —OC(═NR^(b)R^(c),—OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a), —OS(O)₂R^(a), —OS(O)NR^(b)R^(c),—OS(O)₂NR^(b)R^(c), —NR^(b)R^(c), —NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d),—NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d),—NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c),—SR^(a), —S(O)R^(a), —S(O)₂R^(a), —S(O)NR^(b)R^(c), and—S(O)₂NR^(b)R^(c), wherein each R^(a), R^(b), R^(c), and R^(d) isindependently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl,each optionally substituted with one or more, in one embodiment, one,two, three, or four, substituents Q¹; or (iii) R^(b) and R^(c) togetherwith the N atom to which they are attached form heteroaryl orheterocyclyl, optionally substituted with one or more, in oneembodiment, one, two, three, or four, substituents Q¹. As used herein,all groups that can be substituted are “optionally substituted,” unlessotherwise specified.

In one embodiment, each Q¹ is independently selected from the groupconsisting of (a) cyano, halo, and nitro; and (b) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, and heterocyclyl; and (c) —C(O)R^(e), —C(O)OR^(e),—C(O)NR^(f)R^(g), —C(NR^(e))NR^(f)R^(g), —OR^(e), —OC(O)R^(e),—OC(O)OR^(e), —OC(O)NR^(f)R^(g), —OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e),—OS(O)₂R^(e), —OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g), —NR^(f)R^(g),—NR^(e)C(O)R^(h), —NR^(e)C(O)OR^(h), —NR^(e)C(O)NR^(f)R^(g),—NR^(e)C(═NR^(h))NR^(f)R^(g), —NR^(e)S(O)R^(h), —NR^(e)S(O)₂R^(h),—NR^(e)S(O)NR^(f)R^(g), —NR^(e)S(O)₂NR^(f)R^(g), —SR^(e), —S(O)R^(e),—S(O)₂R^(e), —S(O)NR^(f)R^(g), and —S(O)₂NR^(f)R^(g); wherein eachR^(e), R^(f), R^(g), and R^(h) is independently (i) hydrogen; (ii) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl; or (iii) R^(f) and R^(g) togetherwith the N atom to which they are attached form heteroaryl orheterocyclyl.

In certain embodiments, “optically active” and “enantiomerically active”refer to a collection of molecules, which has an enantiomeric excess ofno less than about 50%, no less than about 70%, no less than about 80%,no less than about 90%, no less than about 91%, no less than about 92%,no less than about 93%, no less than about 94%, no less than about 95%,no less than about 96%, no less than about 97%, no less than about 98%,no less than about 99%, no less than about 99.5%, or no less than about99.8%. In certain embodiments, the compound comprises about 95% or moreof the desired enantiomer and about 5% or less of the less preferredenantiomer based on the total weight of the racemate in question.

In describing an optically active compound, the prefixes R and S areused to denote the absolute configuration of the molecule about itschiral center(s). The (+) and (−) are used to denote the opticalrotation of the compound, that is, the direction in which a plane ofpolarized light is rotated by the optically active compound. The (−)prefix indicates that the compound is levorotatory, that is, thecompound rotates the plane of polarized light to the left orcounterclockwise. The (+) prefix indicates that the compound isdextrorotatory, that is, the compound rotates the plane of polarizedlight to the right or clockwise. However, the sign of optical rotation,(+) and (−), is not related to the absolute configuration of themolecule, R and S.

The term “solvate” refers to a compound provided herein or a saltthereof, which further includes a stoichiometric or non-stoichiometricamount of solvent bound by non-covalent intermolecular forces. Where thesolvent is water, the solvate is a hydrate.

The phrase “an enantiomer, a mixture of enantiomers, or a mixture of twoor more diastereomers thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof” has the same meaning as the phrase“a single enantiomer, a mixture of enantiomers, or a mixture ofdiastereomers of the compound referenced therein; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug of the compound referencedtherein, or an enantiomer, a mixture of enantiomers, or a mixture ofdiastereomers of the compound referenced therein.”

Compounds

In one embodiment, provided herein is a compound of Formula IA, IB, orIC:

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof; or a pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof; wherein:

each R¹ and R² is independently (a) hydrogen, cyano, halo, or nitro; (b)C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl,C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a),—C(O)OR^(1b), —C(O)NR^(1b)R^(1c), —C(NR^(a))NR^(1b)R^(1c), —OR^(1a),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); wherein each R^(1a), R^(1b),R^(1c), and R^(1d) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl; or (iii) R^(1b) and R^(1c) together withthe N atom to which they are attached form heterocyclyl;

each R³ and R⁴ is independently hydrogen or C₁₋₆ alkyl; or R³ and R⁴ arelinked together to form a bond, C₁₋₆ alkylene, C₁₋₆ heteroalkylene, C₂₋₆alkenylene, or C₂₋₆ heteroalkenylene;

each R⁵ is independently C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, C₃₋₇ cycloalkyl-C₁₋₆ alkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, heteroaryl-C₁₋₆ alkyl, heterocyclyl, heterocyclyl-C₁₋₆alkyl, or —NR^(5m)R^(5n), where R^(5m) and R^(5n) are each independentlyhydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl;

each R⁶ is independently hydrogen or C₁₋₆ alkyl;

each A, B, D, and E is independently a bond, C, O, N, S, NR⁷, C(O), CR⁷,or CR⁷R^(7′), where each R⁷ and R^(7′) is independently hydrogen, halo,C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl; wherein the bonds between A,B, D, and E may be saturated or unsaturated; with the proviso that nomore than one of A, B, D, and E are a bond;

each Q is C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene, C₃₋₇cycloalkylene, C₆₋₁₄ arylene, heteroarylene, or heterocyclylene;

each T¹ is independently a bond, C₁₋₆ alkylene, —O—, or —NR⁸—;

each T² is independently a bond, C₁₋₆ alkylene, or —NR⁸—;

with the proviso that at least one of the two atoms that are directlyattached to the —SO₂— group is nitrogen;

each R⁸ is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆alkynyl; and

X, Y, and Z are each independently a nitrogen atom or CR⁹, with theproviso that at least two of X, Y, and Z are nitrogen atoms; where R⁹ ishydrogen or C₁₋₆ alkyl;

wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene,heteroalkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl,arylene, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene inR¹, R², R³, R⁴, R⁵, R⁶, R⁷, R^(7′), R⁸, R⁹, R^(1a), R^(1b), R^(1c),R^(1d), R^(5m), R^(5n), Q, T¹, and T², is optionally substituted withone or more groups, in one embodiment, one, two, three, or four groups,each independently selected from (a) cyano, halo, and nitro; (b) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, and heterocyclyl, each optionally substituted withone or more, in one embodiment, one, two, three, or four, substituentsQ¹; and (c) —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(c),—C(NR^(a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a), —OC(O)OR^(a),—OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a), —OS(O)₂R^(a),—OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c), —NR^(b)R^(c), —NR^(a)C(O)R^(d),—NR^(a)C(O)OR^(d), —NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c),—NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c),—NR^(a)S(O)₂NR^(b)R^(c), —SR^(a), —S(O)R^(a), —S(O)₂R^(a),—S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c), wherein each R^(a), R^(b),R^(c), and R^(d) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl, each optionally substituted with one ormore, in one embodiment, one, two, three, or four, substituents Q¹; or(iii) R^(b) and R^(c) together with the N atom to which they areattached form heterocyclyl, optionally substituted with one or more, inone embodiment, one, two, three, or four, substituents Q¹;

wherein each Q¹ is independently selected from the group consisting of(a) cyano, halo, and nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, andheterocyclyl; and (c) —C(O)R^(e), —C(O)OR^(e), —C(O)NR^(f)R^(g),—C(NR^(e))NR^(f)R^(g), —OR^(e), —OC(O)R^(e), —OC(O)OR^(e),—OC(O)NR^(f)R^(g), —OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e), —OS(O)₂R^(e),—OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g), —NR^(f)R^(g), —NR^(c)C(O)R^(h),—NR^(e)C(O)OR^(h), —NR^(e)C(O)NR^(f)R^(g), —NR^(e)C(═NR^(h))NR^(f)R^(g),—NR^(e)S(O)R^(h), —NR^(e)S(O)₂R^(h), —NR^(e)S(O)NR^(f)R^(g),—NR^(e)S(O)₂NR^(f)R^(g), —SR^(e), —S(O)R^(c), —S(O)₂R^(c),—S(O)NR^(f)R^(g), and —S(O)₂NR^(f)R^(g); wherein each R^(e), R^(f),R^(g), and R^(h) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl; or (iii) R^(f) and R^(g) together with theN atom to which they are attached form heterocyclyl.

In another embodiment, provided herein is a compound of Formula IA, IB,or IC:

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof; or a pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof; wherein:

each R¹ and R² is independently (a) hydrogen, cyano, halo, or nitro; (b)C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl,C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a),—C(O)OR^(1b), —C(O)NR^(1b)R^(1c), —C(NR^(a))NR^(1b)R^(1c), —OR^(1a),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); wherein each R^(1a), R^(1b),R^(1c), and R^(1d) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl; or (iii) R^(1b) and R^(1c) together withthe N atom to which they are attached form heterocyclyl;

each R³ and R⁴ is independently hydrogen or C₁₋₆ alkyl; or R³ and R⁴ arelinked together to form a bond, C₁₋₆ alkylene, C₁₋₆ heteroalkylene, C₂₋₆alkenylene, or C₂₋₆ heteroalkenylene;

each R⁵ is independently C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl;

each R⁶ is independently hydrogen or C₁₋₆ alkyl;

each A, B, D, and E is independently a bond, C, O, N, S, NR⁷, CR⁷, orCR⁷R^(7′), where each R⁷ and R^(7′) is independently hydrogen, halo,C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl; wherein the bonds between A,B, D, and E may be saturated or unsaturated; with the proviso that nomore than one of A, B, D, and E are a bond;

each Q is C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene, C₃₋₇cycloalkylene, C₆₋₁₄ arylene, heteroarylene, or heterocyclylene;

each T¹ is independently a bond, —O—, or —NR⁸—;

each T² is independently a bond or —NR⁸—, with the proviso that the atomthat is attached to —SO₂R⁵ is nitrogen;

each R⁸ is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆alkynyl; and

X, Y, and Z are each independently a nitrogen atom or CR⁹, with theproviso that at least two of X, Y, and Z are nitrogen atoms; where R⁹ ishydrogen or C₁₋₆ alkyl;

wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene,heteroalkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl,arylene, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene inR¹, R², R³, R⁴, R⁵, R⁶, R⁷, R^(7′), R⁸, R⁹, R^(1a), R^(1b), R^(1c),R^(1d), and Q is optionally substituted with one or more groups, in oneembodiment, one, two, three, or four groups, each independently selectedfrom (a) cyano, halo, and nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, andheterocyclyl, each optionally substituted with one or more, in oneembodiment, one, two, three, or four, substituents Q¹; and (c)—C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(c), —C(NR^(a))NR^(b)R^(c),—OR^(a), —OC(O)R^(a), —OC(O)OR^(a), —OC(O)NR^(b)R^(c), —OC(═NR^(b)R^(c),—OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a), —OS(O)₂R^(a), —OS(O)NR^(b)R^(c),—OS(O)₂NR^(b)R^(c), —NR^(b)R^(c), —NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d),—NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d),—NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c),—SR^(a), —S(O)R^(a), —S(O)₂R^(a), —S(O)NR^(b)R^(c), and—S(O)₂NR^(b)R^(c), wherein each R^(a), R^(b), R^(c), and R^(d) isindependently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, C₆₋₁₄ in one embodiment, one, two, three, or four,substituents Q¹; or (iii) R^(b) and R^(c) together with the N atom towhich they are attached form heterocyclyl, optionally substituted withone or more, in one embodiment, one, two, three, or four, substituentsQ¹;

wherein each Q¹ is independently selected from the group consisting of(a) cyano, halo, and nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, andheterocyclyl; and (c) —C(O)R^(e), —C(O)OR^(e), —C(O)NR^(f)R^(g),—C(NR^(e))NR^(f)R^(g), —OR^(e), —OC(O)R^(e), —OC(O)OR^(e),—OC(O)NR^(f)R^(g), —OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e), —OS(O)₂R^(e),—OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g), —NR^(f)R^(g), —NR^(e)C(O)R^(h),—NR^(e)C(O)OR^(h), —NR^(e)C(O)NR^(f)R^(g), —NR^(e)C(═NR^(h))NR^(f)R^(g),—NR^(e)S(O)R^(h), —NR^(e)S(O)₂R^(h), —NR^(e)S(O)NR^(f)R^(g),—NR^(e)S(O)₂NR^(f)R^(g), —SR^(e), —S(O)R^(e), —S(O)₂R^(e),—S(O)NR^(f)R^(g), and —S(O)₂NR^(f)R^(g); wherein each R^(e), R^(f),R^(g), and R^(h) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl; or (iii) R^(f) and R^(g) together with theN atom to which they are attached form heterocyclyl.

In yet another embodiment, provided herein is a compound of Formula IA,IB, or IC:

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof; or a pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof; wherein:

each R¹ and R² is independently (a) hydrogen, cyano, halo, or nitro; (b)C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl,C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a),—C(O)OR^(1b), —C(O)NR^(1b)R^(1c), —C(NR^(a))NR^(1b)R^(1c), —OR^(1a),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); wherein each R^(1a), R^(1b),R^(1c), and R^(1d) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl, each optionally substituted with one ormore, in one embodiment, one, two, three, or four, substituents Q¹; or(iii) R^(1b) and R^(1c) together with the N atom to which they areattached form heterocyclyl, optionally substituted with one or more, inone embodiment, one, two, three, or four, substituents Q¹;

each R³ and R⁴ is independently hydrogen or C₁₋₆ alkyl;

each R⁵ is independently C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl;

each R⁶ is independently hydrogen or C₁₋₆ alkyl;

each A, B, D, and E is independently (i) a bond; (ii) a nitrogen,oxygen, or sulfur atom; or (iii) CR⁷, where R⁷ is hydrogen, halo, C₁₋₆alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl; wherein the bonds between A, B, D,and E may be saturated or unsaturated; with the proviso that no morethan one of A, B, D, and E are a bond;

each Q is C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene, C₃₋₇cycloalkylene, C₆₋₁₄ arylene, heteroarylene, or heterocyclylene;

each T¹ is independently a bond, —O—, or —NR⁸—;

each T² is independently a bond or —NR⁸—, with the proviso that the atomthat is attached to —SO₂R⁵ is nitrogen;

each R⁸ is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆alkynyl; and

X, Y, and Z are each independently a nitrogen atom or CR⁹, with theproviso that at least two of X, Y, and Z are nitrogen atoms; where R⁹ ishydrogen or C₁₋₆ alkyl;

wherein each alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene,cycloalkyl, cycloalkylene, aryl, arylene, heteroaryl, heteroarylene,heterocyclyl, and heterocyclylene is optionally substituted with one ormore groups, each independently selected from (a) cyano, halo, andnitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, and heterocyclyl, each optionallysubstituted with one or more, in one embodiment, one, two, three, orfour, substituents Q¹; and (c) —C(O)R^(a), —C(O)OR^(a),—C(O)NR^(b)R^(c), —C(NR^(a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a),—OC(O)OR^(a), —OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a),—OS(O)₂R^(a), —OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c), —NR^(b)R^(c),—NR^(a)(O)R^(d), —NR^(a)C(O)OR^(d), —NR^(a)C(O)NR^(b)R^(c),—NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d),—NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c), —SR^(a), —S(O)R^(a),—S(O)₂R^(a), —S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c), wherein eachR^(a), R^(b), R^(c), and R^(d) is independently (i) hydrogen; (ii) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl, each optionally substituted withone or more, in one embodiment, one, two, three, or four, substituentsQ¹; or (iii) R^(b) and R^(c) together with the N atom to which they areattached form heterocyclyl, optionally substituted with one or more, inone embodiment, one, two, three, or four, substituents Q¹;

wherein each Q¹ is independently selected from the group consisting of(a) cyano, halo, and nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, andheterocyclyl; and (c) —C(O)R^(e), —C(O)OR^(e), —C(O)NR^(f)R^(g),—C(NR^(e))NR^(f)R^(g), —OR^(e), —OC(O)R^(e), —OC(O)OR^(e),—OC(O)NR^(f)R^(g), —OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e), —OS(O)₂R^(e),—OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g), —NR^(f)R^(g), —NR^(e)C(O)R^(h),—NR^(e)C(O)OR^(h), —NR^(e)C(O)NR^(f)R^(g), —NR^(e)C(═NR^(h))NR^(f)R^(g),—NR^(e)S(O)R^(h), —NR^(e)S(O)₂R^(h), —NR^(e)S(O)NR^(f)R^(g),—NR^(e)S(O)₂NR^(f)R^(g), —SR^(e), —S(O)R^(e), —S(O)₂R^(e),—S(O)NR^(f)R^(g), and —S(O)₂NR^(f)R^(g); wherein each R^(e), R^(f),R^(g), and R^(h) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl; or (iii) R^(f) and R^(g) together with theN atom to which they are attached form heterocyclyl.

In yet another embodiment, provided herein is a compound of Formula Ia,Ib, or Ic:

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof; or a pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof; wherein:

each R¹ and R² is independently (a) hydrogen, cyano, halo, or nitro; (b)C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl,C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a),—C(O)OR^(1b), —C(O)NR^(1b)R^(1c), —C(NR^(a))NR^(1b)R^(1c), —OR^(1a),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); wherein each R^(1a), R^(1b),R^(1c), and R^(1d) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl; or (iii) R^(1b) and R^(1c) together withthe N atom to which they are attached form heterocyclyl;

each R³ and R⁴ is independently hydrogen or C₁₋₆ alkyl; or R³ and R⁴ arelinked together to form a bond, C₁₋₆ alkylene, C₁₋₆ heteroalkylene, C₂₋₆alkenylene, or C₂₋₆ heteroalkenylene;

each R⁵ is independently C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl;

each R⁶ is independently hydrogen or C₁₋₆ alkyl;

each A, B, D, and E is independently a bond, C, O, N, S, NR⁷, CR⁷, orCR⁷R^(7′), where each R⁷ and R^(7′) is independently hydrogen, halo,C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl; wherein the bonds between A,B, D, and E may be saturated or unsaturated; with the proviso that nomore than one of A, B, D, and E are a bond;

each Q is C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene, C₃₋₇cycloalkylene, C₆₋₁₄ arylene, heteroarylene, or heterocyclylene;

each T¹ is independently a bond, —O—, or —NR⁸—;

each T² is independently a bond or —NR⁸—, with the proviso that the atomthat is attached to —SO₂R⁵ is nitrogen;

each R⁸ is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆alkynyl; and

X, Y, and Z are each independently a nitrogen atom or CR⁹, with theproviso that at least two of X, Y, and Z are nitrogen atoms; where R⁹ ishydrogen or C₁₋₆ alkyl;

wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene,heteroalkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl,arylene, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene inR¹, R², R³, R⁴, R⁵, R⁶, R⁷, R^(7′), R⁸, R⁹, R^(1a), R^(1b), R^(1c),R^(1d), and Q is optionally substituted with one or more groups, in oneembodiment, one, two, three, or four groups, each independently selectedfrom (a) cyano, halo, and nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, andheterocyclyl, each optionally substituted with one or more, in oneembodiment, one, two, three, or four, substituents Q¹; and (c)—C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(c), —C(NR^(a))NR^(b)R^(c),—OR^(a), —OC(O)R^(a), —OC(O)OR^(a), —OC(O)NR^(b)R^(c),—OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a), —OS(O)₂R^(a), —OS(O)NR^(b)R^(c),—OS(O)₂NR^(b)R^(c), —NR^(b)R^(c), —NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d),—NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d),—NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c),—SR^(a), —S(O)R^(a), —S(O)₂R^(a), —S(O)NR^(b)R^(c), and—S(O)₂NR^(b)R^(c), wherein each R^(a), R^(b), R^(c), and R^(d) isindependently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl,each optionally substituted with one or more, in one embodiment, one,two, three, or four, substituents Q¹; or (iii) R^(b) and R^(c) togetherwith the N atom to which they are attached form heterocyclyl, optionallysubstituted with one or more, in one embodiment, one, two, three, orfour, substituents Q¹;

wherein each Q¹ is independently selected from the group consisting of(a) cyano, halo, and nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, andheterocyclyl; and (c) —C(O)R^(e), —C(O)OR^(e), —C(O)NR^(f)R^(g),—C(NR^(e))NR^(f)R^(g), —OR^(e), —OC(O)R^(e), —OC(O)OR^(e),—OC(O)NR^(f)R^(g), —OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e), —OS(O)₂R^(e),—OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g), —NR^(f)R^(g), —NR^(e)C(O)R^(h),—NR^(e)C(O)OR^(h), —NR^(e)C(O)NR^(f)R^(g), —NR^(e)C(═NR^(h))NR^(f)R^(g),—NR^(e)S(O)R^(h), —NR^(e)S(O)₂R^(h), —NR^(e)S(O)NR^(f)R^(g),—NR^(e)S(O)₂NR^(f)R^(g), —SR^(e), —S(O)R^(e), —S(O)₂R^(e),—S(O)NR^(f)R^(g), and —S(O)₂NR^(f)R^(g); wherein each R^(e), R^(f),R^(g), and R^(h) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl; or (iii) R^(f) and R^(g) together with theN atom to which they are attached form heterocyclyl.

In yet another embodiment, provided herein is a compound of Formula Ia,Ib, or Ic:

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof; or a pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof; wherein:

each R¹ and R² is independently (a) hydrogen, cyano, halo, or nitro; (b)C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl,C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a),—C(O)OR^(1b), —C(O)NR^(1b)R^(1c), —C(NR^(a))NR^(1b)R^(1c), —OR^(1a),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); wherein each R¹, R^(1b),R^(1c), and R^(1d) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl, each optionally substituted with one ormore, in one embodiment, one, two, three, or four, substituents Q¹; or(iii) R^(1b) and R^(1c) together with the N atom to which they areattached form heterocyclyl, optionally substituted with one or more, inone embodiment, one, two, three, or four, substituents Q¹;

each R³ and R⁴ is independently hydrogen or C₁₋₆ alkyl;

each R⁵ is independently C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl;

each R⁶ is independently hydrogen or C₁₋₆ alkyl;

each A, B, D, and E is independently (i) a bond; (ii) a nitrogen,oxygen, or sulfur atom; or (iii) CR⁷, where R⁷ is hydrogen, halo, C₁₋₆alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl; wherein the bonds between A, B, D,and E may be saturated or unsaturated; with the proviso that no morethan one of A, B, D, and E are a bond;

each Q is C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene, C₃₋₇cycloalkylene, C₆₋₁₄ arylene, heteroarylene, or heterocyclylene;

each T¹ is independently a bond, —O—, or —NR⁸—;

each T² is independently a bond or —NR⁸—, with the proviso that the atomthat is attached to —SO₂R⁵ is nitrogen;

each R⁸ is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆alkynyl; and

X, Y, and Z are each independently a nitrogen atom or CR⁹, with theproviso that at least two of X, Y, and Z are nitrogen atoms; where R⁹ ishydrogen or C₁₋₆ alkyl;

wherein each alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene,cycloalkyl, cycloalkylene, aryl, arylene, heteroaryl, heteroarylene,heterocyclyl, and heterocyclylene is optionally substituted with one ormore groups, each independently selected from (a) cyano, halo, andnitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, and heterocyclyl, each optionallysubstituted with one or more, in one embodiment, one, two, three, orfour, substituents Q¹; and (c) —C(O)R^(a), —C(O)OR^(a),—C(O)NR^(b)R^(c), —C(NR^(a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a),—OC(O)OR^(a), —OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a),—OS(O)₂R^(a), —OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c), —NR^(b)R^(c),—NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d), —NR^(a)C(O)NR^(b)R^(c),—NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d),—NR^(a)S(O)NR^(b)R^(e), —NR^(a)S(O)₂NR^(b)R^(c), —SR^(a), —S(O)R^(a),—S(O)₂R^(a), —S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c), wherein eachR^(a), R^(b), R^(c), and R^(d) is independently (i) hydrogen; (ii) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl, each optionally substituted withone or more, in one embodiment, one, two, three, or four, substituentsQ¹; or (iii) R^(b) and R^(e) together with the N atom to which they areattached form heterocyclyl, optionally substituted with one or more, inone embodiment, one, two, three, or four, substituents Q¹;

wherein each Q¹ is independently selected from the group consisting of(a) cyano, halo, and nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, andheterocyclyl; and (c) —C(O)R^(e), —C(O)OR^(e), —C(O)NR^(f)R^(g),—C(NR^(e))NR^(f)R^(g), —OR^(e), —OC(O)R^(e), —OC(O)OR^(e),—OC(O)NR^(f)R^(g), —OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e), —OS(O)₂R^(e),—OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g), —NR^(f)R^(g), —NR^(e)C(O)R^(h),—NR^(e)C(O)OR^(h), —NR^(e)C(O)NR^(f)R^(g), —NR^(e)C(═NR^(h))NR^(f)R^(g),—NR^(e)S(O)R^(h), —NR^(c)S(O)₂R^(h), —NR^(e)S(O)NR^(f)R^(g),—NR^(e)S(O)₂NR^(f)R^(g), —SR^(e), —S(O)R^(e), —S(O)₂R^(e),—S(O)NR^(f)R^(g), and —S(O)₂NR^(f)R^(g); wherein each R^(e), R^(f),R^(g), and R^(h) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl; or (iii) R^(f) and R^(g) together with theN atom to which they are attached form heterocyclyl.

In one embodiment, in Formula Ia, Ib, or Ic,

each R¹ and R² is independently hydrogen, —OR^(1a), or —NR^(1b)R^(1c);where R^(1a), R^(1b), and R^(1c) are each independently (a) hydrogen; or(b) C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl, each optionallysubstituted with one or more substituents Q¹; or R^(1b) and R^(1c)together with the N atom to which they are attached form heterocyclyl,optionally substituted with one or more substituents Q¹;

each R³ and R⁴ is independently hydrogen or C₁₋₆ alkyl, optionallysubstituted with one or more substituents Q¹;

each R⁵ is independently C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl, eachoptionally substituted with one or more substituents Q¹;

each R⁶ is independently C₁₋₆ alkyl, optionally substituted with one ormore substituents Q¹;

each A, B, D, and E is independently (i) a bond; (ii) a nitrogen,oxygen, or sulfur atom; or (iii) CH; wherein the bonds between A, B, D,and E may be saturated or unsaturated; with the proviso that no morethan one of A, B, D, and E are a bond;

Q is C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene, C₃₋₇cycloalkylene, C₆₋₁₄ arylene, heteroarylene, or heterocyclylene, eachoptionally substituted with one or more substituents Q¹;

each T¹ is independently a bond, —O—, or —NR⁸—;

each T² is independently a bond or —NR⁸—, with the proviso that the atomthat is attached to —SO₂R⁵ is nitrogen;

each R⁸ is independently (a) hydrogen; or (b) C₁₋₆ alkyl, C₂₋₆ alkenyl,or C₂₋₆ alkynyl, each optionally substituted with one or moresubstituents Q¹; and

X, Y, and Z are each independently a nitrogen atom or CR⁹, with theproviso that at least two of X, Y, and Z are nitrogen atoms; where R⁹ ishydrogen or C₁₋₆ alkyl, optionally substituted with one or moresubstituents Q¹.

In another embodiment, in Formula Ia, Ib, or Ic,

each R¹ and R² is independently hydrogen, —OR^(1a), or —NR^(1b)R^(1c);where R^(1a), R^(1b), and R^(1c) are each independently (a) hydrogen; or(b) C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl, each optionallysubstituted with one or more substituents Q¹, each independentlyselected from the group consisting of —OR^(e) and —NR^(f)R^(g);

each R³ and R⁴ is independently hydrogen or C₁₋₆ alkyl, optionallysubstituted with one or more substituents Q¹, each independentlyselected from the group consisting of —OR^(e) and —NR^(f)R^(g);

each R⁵ is independently C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl, eachoptionally substituted with one or more substituents Q¹, eachindependently selected from the group consisting of halo, heteroaryl,heterocyclyl, —OR^(e), and —NR^(f)R^(g);

each R⁶ is independently C₁₋₆ alkyl, optionally substituted with one ormore substituents Q¹, each independently selected from the groupconsisting of —OR^(e) and —NR^(f)R^(g);

each A, B, D, and E is independently (i) a bond; (ii) a nitrogen,oxygen, or sulfur atom; or (iii) CH; wherein the bonds between A, B, D,and E may be saturated or unsaturated; with the proviso that no morethan one of A, B, D, and E are a bond;

Q is C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene, C₃₋₇cycloalkylene, C₆₋₁₄ arylene, heteroarylene, or heterocyclylene, eachoptionally substituted with one or more substituents Q¹;

each T¹ is independently a bond, —O—, or —NR⁸—;

each T² is independently a bond or —NR⁸—, with the proviso that the atomthat is attached to —SO₂R⁵ is nitrogen;

each R⁸ is independently (a) hydrogen; or (b) C₁₋₆ alkyl, C₂₋₆ alkenyl,or C₂₋₆ alkynyl, each optionally substituted with one or moresubstituents Q¹, each independently selected from the group consistingof cyano, —C(O)R^(e), —C(O)OR^(e), —C(O)NR^(f)R^(g), —OR^(e),—OC(O)R^(e), —OC(O)OR^(e), —OC(O)NR^(f)R^(g), —NR^(f)R^(g),—NR^(e)C(O)R^(h), —NR^(e)C(O)OR^(f), —S(O)₂R^(e), and —S(O)₂NR^(f)R^(g);

X, Y, and Z are each independently a nitrogen atom or CR⁹, with theproviso that at least two of X, Y, and Z are nitrogen atoms; where R⁹ ishydrogen or C₁₋₆ alkyl; and

each R^(e), R^(f), R^(g), and R^(h) is independently hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl.

In yet another embodiment, in Formula Ia, Ib, or Ic,

each R¹ is independently hydrogen or —OR^(1a), where R^(1a) is C₁₋₆alkyl, optionally substituted with one or more —NR^(f)R^(g); where R^(f)and R^(g) are each independently hydrogen or C₁₋₆ alkyl;

each R², R³, and R⁴ is independently hydrogen or C₁₋₆ alkyl;

each R⁵ is independently C₁₋₆ alkyl or C₁₋₆ alkenyl, each optionallysubstituted with one or more substituents Q¹, each independentlyselected from the group consisting of chloro, heterocyclyl, and—NR^(f)R^(g);

R⁶ is C₁₋₆ alkyl, optionally substituted with one or more halo;

A, B, D, and E are each independently (i) a bond; (ii) a nitrogen,oxygen, or sulfur atom; or (iii) CH; wherein the bonds between A, B, D,and E may be saturated or unsaturated; with the proviso that no morethan one of A, B, D, and E are a bond;

Q is heterocyclylene;

each T¹ is independently a bond, —O—, or —NR⁸—;

each T² is independently a bond or —NR⁸—, with the proviso that the atomthat is attached to —SO₂R⁵ is nitrogen;

each R⁸ is independently (a) hydrogen; or (b) C₁₋₆ alkyl, C₂₋₆ alkenyl,or C₂₋₆ alkynyl, each optionally substituted with one or moresubstituents Q¹, each independently selected from the group consistingof cyano, —C(O)R^(e), —C(O)OR^(e), —C(O)NR^(f)R^(g), —OR^(e),—OC(O)R^(e), —OC(O)OR^(e), —OC(O)NR^(f)R^(g), —NR^(f)R^(g),—NR^(e)C(O)R^(h), —NR^(e)C(O)OR^(f), —S(O)₂R^(e), and —S(O)₂NR^(f)R^(g);

X, Y, and Z are each independently a nitrogen atom or CR⁹, with theproviso that at least two of X, Y, and Z are nitrogen atoms; and

R⁹ is independently hydrogen or C₁₋₆ alkyl.

In yet another embodiment, in Formula Ia, Ib, or Ic,

each R¹ is independently hydrogen, methoxy, or dimethylaminopropoxy;

R², R³, and R⁴ are hydrogen;

each R⁵ is independently methyl, ethenyl, chloropropyl,dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl,morpholinylmethyl, morpholinylethyl, morpholinylpropyl,(methylpiperazinyl)methyl, (methylpiperazinyl)ethyl,(methylpiperazinyl)propyl, (methylsulfonylpiperazinylmethyl,(methylsulfonylpiperazinyl)ethyl, or (methylsulfonylpiperazinyl)propyl;

R⁶ is difluoromethyl;

A, B, D, and E are each independently (i) a bond; (ii) a nitrogen,oxygen, or sulfur atom; or (iii) CH; wherein the bonds between A, B, D,and E may be saturated or unsaturated; with the proviso that no morethan one of A, B, D, and E are a bond;

Q is azetidinylene, cyclopropylene, cyclobutylene, cyclopentylene,cyclohexylene, pyrrollidinylene, pyrrolylene, pyrazolylene,piperidinylene, piperazinylene, phenylene, thiazolylylene, orpyridylene;

each T¹ is independently a bond, —O—, or —NR⁸—;

each T² is independently a bond or —NR⁸—, with the proviso that the atomthat is attached to —SO₂R⁵ is nitrogen;

each R⁸ is independently hydrogen or methyl; and

X, Y, and Z are each independently a nitrogen atom or CH, with theproviso that at least two of X, Y, and Z are nitrogen atoms.

In yet another embodiment, in Formula Ia, Ib, or Ic,

each R¹ is independently hydrogen, methoxy, or 3-dimethylaminopropoxy;

R², R³, and R⁴ are hydrogen;

each R⁵ is independently methyl, ethenyl, 3-chloropropyl,dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylpropylamino,4-morpholinylmethyl, 2-(4-morpholinyl)ethyl, 3-(4-morpholinyl)propyl,(4-methyl-1-piperazinyl)methyl, 2-(4-methyl-1-piperazinyl)ethyl,3-(4-methyl-1-piperazinyl)propyl,4-(methylsulfonyl)-1-piperazinyl-methyl,2-(4-(methylsulfonyl)-1-piperazinyl)ethyl, or3-(4-(methylsulfonyl)-1-piperazinyl)propyl;

R⁶ is difluoromethyl;

A, B, D, and E are each independently (i) a bond; (ii) a nitrogen,oxygen, or sulfur atom; or (iii) CH; wherein the bonds between A, B, D,and E may be saturated or unsaturated; with the proviso that no morethan one of A, B, D, and E are a bond;

Q is 1,4-piperidinylene or 1,4-piperazinylene;

each T¹ is independently a bond, —O—, or —NR⁸—;

each T² is independently a bond or —NR⁸—, with the proviso that the atomthat is attached to —SO₂R⁵ is nitrogen;

each R⁸ is independently hydrogen or methyl; and

X, Y, and Z are each independently a nitrogen atom or CH, with theproviso that at least two of X, Y, and Z are nitrogen atoms.

In yet another embodiment, in Formula Ia, Ib, or Ic,

each R¹ is independently hydrogen, methoxy, or 3-dimethylaminopropoxy;

R², R³, and R⁴ are hydrogen;

each R⁵ is independently methyl, ethenyl, 3-chloropropyl,dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylpropyl,4-morpholinylmethyl, 2-(4-morpholinyl)ethyl, 3-(4-morpholinyl)propyl,(4-methyl-1-piperazinyl)methyl, 2-(4-methyl-1-piperazinyl)ethyl,3-(4-methyl-1-piperazinyl)propyl,4-(methylsulfonyl)-1-piperazinyl-methyl,2-(4-(methylsulfonyl)-1-piperazinyl)ethyl, or3-(4-(methylsulfonyl)-1-piperazinyl)propyl;

R⁶ is difluoromethyl;

A, B, D, and E are each independently (i) a bond; (ii) a nitrogen,oxygen, or sulfur atom; or (iii) CH; wherein the bonds between A, B, D,and E may be saturated or unsaturated; with the proviso that no morethan one of A, B, D, and E are a bond;

Q is 1,4-piperidinylene or 1,4-piperazinylene;

each T¹ is independently a bond, —O—, or —NR⁸—;

each T² is independently a bond or —NR⁸—, with the proviso that the atomthat is attached to —SO₂R⁵ is nitrogen;

each R⁸ is independently hydrogen or methyl; and

X, Y, and Z are each independently a nitrogen atom or CH, with theproviso that at least two of X, Y, and Z are nitrogen atoms.

In yet another embodiment, in Formula Ia, Ib, or Ic,

each R¹ is independently hydrogen or —OR^(1a), where R^(1a) is C₁₋₆alkyl, optionally substituted with one or more —NR^(f)R^(g); where R^(f)and R^(g) are each independently hydrogen or C₁₋₆ alkyl;

each R² is independently hydrogen, C₁₋₆ alkyl, or —NR^(1b)R^(1c); whereR^(1b) and R^(1c) are each independently (a) hydrogen; or (b) C₁₋₆alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl, each optionally substituted withone or more substituents Q¹, each independently selected from the groupconsisting of —OR^(e) and —NR^(f)R^(g);

each R³ and R⁴ is independently hydrogen or C₁₋₆ alkyl;

each R⁵ is independently C₁₋₆ alkyl or C₁₋₆ alkenyl, each optionallysubstituted with one or more substituents Q¹, each independentlyselected from the group consisting of chloro, heterocyclyl, and—NR^(f)R^(g);

R⁶ is C₁₋₆ alkyl, optionally substituted with one or more halo;

A, B, D, and E are each independently (i) a bond; (ii) a nitrogen,oxygen, or sulfur atom; or (iii) CH; wherein the bonds between A, B, D,and E may be saturated or unsaturated; with the proviso that no morethan one of A, B, D, and E are a bond;

Q is heterocyclylene;

each T¹ is independently a bond, —O—, or —NR⁸—;

each T² is independently a bond or —NR⁸—, with the proviso that the atomthat is attached to —SO₂R⁵ is nitrogen;

each R⁸ is independently (a) hydrogen; or (b) C₁₋₆ alkyl, C₂₋₆ alkenyl,or C₂₋₆ alkynyl, each optionally substituted with one or moresubstituents Q¹, each independently selected from the group consistingof cyano, —C(O)R^(e), —C(O)OR^(e), —C(O)NR^(f)R^(g), —OR^(e),—OC(O)R^(e), —OC(O)OR^(e), —OC(O)NR^(f)R^(g), —NR^(f)R^(g),—NR^(e)C(O)R^(h), —NR^(e)C(O)OR^(f), —S(O)₂R^(e), and —S(O)₂NR^(f)R^(g);

X, Y, and Z are each independently a nitrogen atom or CR⁹, with theproviso that at least two of X, Y, and Z are nitrogen atoms; and

R⁹ is independently hydrogen or C₁₋₆ alkyl.

In yet another embodiment, in Formula Ia, Ib, or Ic,

each R¹ is independently hydrogen, methoxy, or dimethylaminopropoxy;

each R² is independently hydrogen or amino;

R³ and R⁴ are hydrogen;

each R⁵ is independently methyl, ethenyl, chloropropyl,dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl,morpholinylmethyl, morpholinylethyl, morpholinylpropyl,(methylpiperazinyl)methyl, (methylpiperazinyl)ethyl,(methylpiperazinyl)propyl, (methylsulfonylpiperazinylmethyl,(methylsulfonylpiperazinyl)ethyl, or (methylsulfonylpiperazinyl)propyl;

R⁶ is difluoromethyl;

A, B, D, and E are each independently (i) a bond; (ii) a nitrogen,oxygen, or sulfur atom; or (iii) CH; wherein the bonds between A, B, D,and E may be saturated or unsaturated; with the proviso that no morethan one of A, B, D, and E are a bond;

Q is azetidinylene, cyclopropylene, cyclobutylene, cyclopentylene,cyclohexylene, pyrrollidinylene, pyrrolylene, pyrazolylene,piperidinylene, piperazinylene, phenylene, thiazolylylene, orpyridylene;

each T¹ is independently a bond, —O—, or —NR⁸—;

each T² is independently a bond or —NR⁸—, with the proviso that the atomthat is attached to —SO₂R⁵ is nitrogen;

each R⁸ is independently hydrogen or methyl; and

X, Y, and Z are each independently a nitrogen atom or CH, with theproviso that at least two of X, Y, and Z are nitrogen atoms.

In still another embodiment, Formula Ia, Ib, or Ic,

each R¹ is independently hydrogen, methoxy, or 3-dimethylaminopropoxy;

each R² is independently hydrogen or amino;

R³ and R⁴ are hydrogen;

each R⁵ is independently methyl, ethenyl, 3-chloropropyl,dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl,4-morpholinylmethyl, 2-(4-morpholinyl)ethyl, 3-(4-morpholinyl)propyl,(4-methyl-1-piperazinyl)methyl, 2-(4-methyl-1-piperazinyl)ethyl,3-(4-methyl-1-piperazinyl)propyl,4-(methylsulfonyl)-1-piperazinyl-methyl,2-(4-(methylsulfonyl)-1-piperazinyl)ethyl, or3-(4-(methylsulfonyl)-1-piperazinyl)propyl;

R⁶ is difluoromethyl;

A, B, D, and E are each independently (i) a bond; (ii) a nitrogen,oxygen, or sulfur atom; or (iii) CH; wherein the bonds between A, B, D,and E may be saturated or unsaturated; with the proviso that no morethan one of A, B, D, and E are a bond;

Q is 1,3-piperidinylene, 1,4-piperidinylene, or 1,4-piperazinylene;

each T¹ is independently a bond, —O—, or —NR⁸—;

each T² is independently a bond or —NR⁸—, with the proviso that the atomthat is attached to —SO₂R⁵ is nitrogen;

each R⁸ is independently hydrogen or methyl; and

X, Y, and Z are each independently a nitrogen atom or CH, with theproviso that at least two of X, Y, and Z are nitrogen atoms.

In one embodiment, in Formula IA, IB, IC, Ia, Ib, or Ic,

each R¹ and R² is independently hydrogen, —OR^(1a), or —NR^(1b)R^(1c);where R^(1a), R^(1b), and R^(1c) are each independently (a) hydrogen; or(b) C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl, each optionallysubstituted with one or more substituents; or R^(1b) and R^(1c) togetherwith the N atom to which they are attached form heterocyclyl, optionallysubstituted with one or more substituents;

each R³ and R⁴ is independently hydrogen or C₁₋₆ alkyl, optionallysubstituted with one or more substituents; or R³ and R⁴ are linkedtogether to form a bond or C₁₋₆ alkylene, optionally substituted withone or more substituents;

each R⁵ is independently C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl, eachoptionally substituted with one or more substituents;

each R⁶ is independently C₁₋₆ alkyl, optionally substituted with one ormore substituents;

A, B, D, and E are each independently a bond, C, O, N, S, NH, CH, orCH₂; wherein the bonds between A, B, D, and E may be saturated orunsaturated; with the proviso that no more than one of A, B, D, and Eare a bond;

Q is C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene, C₃₋₇cycloalkylene, C₆₋₁₄ arylene, heteroarylene, or heterocyclylene, eachoptionally substituted with one or more substituents;

each T¹ is independently a bond, —O—, or —NR⁸—;

each T² is independently a bond or —NR⁸—, with the proviso that the atomthat is attached to —SO₂R⁵ is nitrogen;

each R⁸ is independently (a) hydrogen; or (b) C₁₋₆ alkyl, C₂₋₆ alkenyl,or C₂₋₆ alkynyl, each optionally substituted with one or moresubstituents; and

X, Y, and Z are each independently a nitrogen atom or CR⁹, with theproviso that at least two of X, Y, and Z are nitrogen atoms; where R⁹ ishydrogen or C₁₋₆ alkyl, optionally substituted with one or moresubstituents.

In another embodiment, in Formula IA, IB, IC, Ia, Ib, or Ic,

each R¹ and R² is independently hydrogen, —OR^(1a), or —NR^(1b)R^(1c);where R^(1a), R^(1b), and R^(1c) are each independently (a) hydrogen; or(b) C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl, each optionallysubstituted with one or more substituents, each independently selectedfrom the group consisting of —OR^(e) and —NR^(f)R^(g);

each R³ and R⁴ is independently hydrogen or C₁₋₆ alkyl, optionallysubstituted with one or more substituents, each independently selectedfrom the group consisting of —OR^(e) and —NR^(f)R^(g); or R³ and R⁴ arelinked together to form a bond or C₁₋₆ alkylene, optionally substitutedwith one or more substituents

each R⁵ is independently C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl, eachoptionally substituted with one or more substituents, each independentlyselected from the group consisting of halo, heteroaryl, heterocyclyl,—OR^(e), and —NR^(f)R^(g), wherein heteroaryl and heterocyclyl arefurther optionally substituted with one or more substituents;

each R⁶ is independently C₁₋₆ alkyl, optionally substituted with one ormore substituents, each independently selected from the group consistingof —OR^(e) and —NR^(f)R^(g);

A, B, D, and E are each independently a bond, C, O, N, S, NH, CH, orCH₂; wherein the bonds between A, B, D, and E may be saturated orunsaturated; with the proviso that no more than one of A, B, D, and Eare a bond;

Q is C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene, C₃₋₇cycloalkylene, C₆₋₁₄ arylene, heteroarylene, or heterocyclylene, eachoptionally substituted with one or more substituents;

each T¹ is independently a bond, —O—, or —NR⁸—;

each T² is independently a bond or —NR⁸—, with the proviso that the atomthat is attached to —SO₂R⁵ is nitrogen;

each R⁸ is independently (a) hydrogen; or (b) C₁₋₆ alkyl, C₂₋₆ alkenyl,or C₂₋₆ alkynyl, each optionally substituted with one or moresubstituents, each independently selected from the group consisting ofcyano, heterocycle, —C(O)R^(e), —C(O)OR^(e), —C(O)NR^(f)R^(g), —OR^(e),—OC(O)R^(e), —OC(O)OR^(e), —OC(O)NR^(f)R^(g), —NR^(f)R^(g),—NR^(e)C(O)R^(h), —NR^(e)C(O)OR^(f), —S(O)₂R^(e), and —S(O)₂NR^(f)R^(g),where heterocyclyl is optionally substituted with one or moresubstituents;

X, Y, and Z are each independently a nitrogen atom or CR⁹, with theproviso that at least two of X, Y, and Z are nitrogen atoms; where R⁹ ishydrogen or C₁₋₆ alkyl; and

each R^(e), R^(f), R^(g), and R^(h) is independently hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl.

In yet another embodiment, in Formula IA, IB, IC, Ia, Ib, or Ic,

each R¹ is independently hydrogen or —OR^(1a), where R^(1a) is C₁₋₆alkyl, optionally substituted with one or more —NR^(f)R^(g); where R^(f)and R^(g) are each independently hydrogen or C₁₋₆ alkyl;

each R² is independently hydrogen or C₁₋₆ alkyl;

R³, and R⁴ is independently hydrogen or C₁₋₆ alkyl; or R³ and R⁴ arelinked together to form a bond or C₁₋₆ alkylene;

each R⁵ is independently C₁₋₆ alkyl or C₁₋₆ alkenyl, each optionallysubstituted with one or more substituents, each independently selectedfrom the group consisting of chloro, heterocyclyl, and —NR^(f)R^(g),wherein heterocyclyl is further optionally substituted with one or moresubstituents, each of which is independently oxo, methyl, ormethylsulfonyl;

R⁶ is C₁₋₆ alkyl, optionally substituted with one or more halo;

A, B, D, and E are each independently a bond, C, O, N, S, NH, CH, orCH₂; wherein the bonds between A, B, D, and E may be saturated orunsaturated; with the proviso that no more than one of A, B, D, and Eare a bond;

Q is heterocyclylene;

each T¹ is independently a bond, —O—, or —NR⁸—;

each T² is independently a bond or —NR⁸—, with the proviso that the atomthat is attached to —SO₂R⁵ is nitrogen;

each R⁸ is independently (a) hydrogen; or (b) C₁₋₆ alkyl, C₂₋₆ alkenyl,or C₂₋₆ alkynyl, each optionally substituted with one or moresubstituents, each independently selected from the group consisting ofcyano, heterocyclyl, —C(O)R^(e), —C(O)OR^(e), —C(O)NR^(f)R^(g), —OR^(e),—OC(O)R^(e), —OC(O)OR^(e), —OC(O)NR^(f)R^(g), —NR^(f)R^(g),—NR^(e)C(O)R^(h), —NR^(e)C(O)OR^(f), —S(O)₂R^(e), and —S(O)₂NR^(f)R^(g),where heterocyclyl is optionally substituted with one or moresubstituents;

X, Y, and Z are each independently a nitrogen atom or CR⁹, with theproviso that at least two of X, Y, and Z are nitrogen atoms; and

R⁹ is independently hydrogen or C₁₋₆ alkyl.

In yet another embodiment, in Formula IA, IB, IC, Ia, Ib, or Ic,

each R¹ is independently hydrogen, methoxy, or dimethylaminopropoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen; or R³ and R⁴ are linked together to formmethylene or ethylene;

each R⁵ is independently methyl, ethenyl, chloropropyl,dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl,morpholinylmethyl, morpholinylethyl, morpholinylpropyl,(methylpiperazinyl)methyl, (methylpiperazinyl)ethyl,(methylpiperazinyl)propyl, (methylsulfonylpiperazinylmethyl,(methylsulfonylpiperazinyl)ethyl, (methylsulfonylpiperazinyl)propyl,(oxido-thiomorpholinyl)ethyl, or (dioxido-thiomorpholinyl)ethyl;

R⁶ is difluoromethyl;

A, B, D, and E are each independently a bond, C, O, N, S, NH, CH, orCH₂; wherein the bonds between A, B, D, and E may be saturated orunsaturated; with the proviso that no more than one of A, B, D, and Eare a bond;

Q is azetidinylene, cyclopropylene, cyclobutylene, cyclopentylene,cyclohexylene, pyrrolidinylene, pyrrolylene, pyrazolylene,piperidinylene, piperazinylene, phenylene, thiazolylylene, orpyridylene;

each T¹ is independently a bond, —O—, or —NR⁸—;

each T² is independently a bond or —NR⁸—, with the proviso that the atomthat is attached to —SO₂R⁵ is nitrogen;

each R⁸ is independently hydrogen, methyl, ethenyl, chloropropyl,dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl,morpholinylmethyl, morpholinylethyl, morpholinylpropyl,(methylpiperazinyl)methyl, (methylpiperazinyl)ethyl,(methylpiperazinyl)propyl, (methylsulfonylpiperazinylmethyl,(methylsulfonylpiperazinyl)ethyl, or (methylsulfonylpiperazinyl)propyl;and

X, Y, and Z are each independently a nitrogen atom or CH, with theproviso that at least two of X, Y, and Z are nitrogen atoms.

In yet another embodiment, in Formula IA, IB, IC, Ia, Ib, or Ic,

each R¹ is independently hydrogen, methoxy, or 3-dimethylaminopropoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen; or R³ and R⁴ are linked together to formethylene;

each R⁵ is independently methyl, ethenyl, 3-chloropropyl,dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylpropylamino,4-morpholinylmethyl, 2-(4-morpholinyl)ethyl, 3-(4-morpholinyl)propyl,(4-methyl-1-piperazinyl)methyl, 2-(4-methyl-1-piperazinyl)ethyl,3-(4-methyl-1-piperazinyl)propyl,4-(methylsulfonyl)-1-piperazinyl-methyl,2-(4-(methylsulfonyl)-1-piperazinyl)ethyl,3-(4-(methylsulfonyl)-1-piperazinyl)propyl,3-(1-oxido-thiomorpholin-4-yl)ethyl, or3-(1,1-dioxido-thiomorpholin-4-yl)ethyl;

R⁶ is difluoromethyl;

A, B, D, and E are each independently a bond, C, O, N, S, NH, CH, orCH₂; wherein the bonds between A, B, D, and E may be saturated orunsaturated; with the proviso that no more than one of A, B, D, and Eare a bond;

Q is 1,4-piperidinylene or 1,4-piperazinylene;

each T¹ is independently a bond, —O—, or —NR⁸—;

each T² is independently a bond or —NR⁸—, with the proviso that the atomthat is attached to —SO₂R⁵ is nitrogen;

each R⁸ is independently hydrogen, methyl, ethenyl, chloropropyl,dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl,morpholinylmethyl, morpholinylethyl, morpholinylpropyl,(methylpiperazinyl)methyl, (methylpiperazinyl)ethyl,(methylpiperazinyl)propyl, (methylsulfonylpiperazinylmethyl,(methylsulfonylpiperazinyl)ethyl, or (methylsulfonylpiperazinyl)propyl;and

X, Y, and Z are each independently a nitrogen atom or CH, with theproviso that at least two of X, Y, and Z are nitrogen atoms.

In yet another embodiment, in Formula IA, IB, IC, Ia, Ib, or Ic,

each R¹ is independently hydrogen, methoxy, or 3-dimethylaminopropoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen; or R³ and R⁴ are linked together to formethylene;

each R⁵ is independently methyl, ethenyl, 3-chloropropyl,dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylpropyl,4-morpholinylmethyl, 2-(4-morpholinyl)ethyl, 3-(4-morpholinyl)propyl,(4-methyl-1-piperazinyl)methyl, 2-(4-methyl-1-piperazinyl)ethyl,3-(4-methyl-1-piperazinyl)propyl,4-(methylsulfonyl)-1-piperazinyl-methyl,2-(4-(methylsulfonyl)-1-piperazinyl)ethyl,3-(4-(methylsulfonyl)-1-piperazinyl)propyl,3-oxido-thiomorpholin-4-yl)ethyl, or3-(1,1-dioxido-thiomorpholin-4-yl)ethyl;

R⁶ is difluoromethyl;

A, B, D, and E are each independently a bond, C, O, N, S, NH, CH, orCH₂; wherein the bonds between A, B, D, and E may be saturated orunsaturated; with the proviso that no more than one of A, B, D, and Eare a bond;

Q is 1,4-piperidinylene or 1,4-piperazinylene;

each T¹ is independently a bond, —O—, or —NR⁸—;

each T² is independently a bond or —NR⁸—, with the proviso that the atomthat is attached to —SO₂R⁵ is nitrogen;

each R⁸ is independently hydrogen, methyl, ethenyl, chloropropyl,dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl,morpholinylmethyl, morpholinylethyl, morpholinylpropyl,(methylpiperazinyl)methyl, (methylpiperazinyl)ethyl,(methylpiperazinyl)propyl, (methylsulfonylpiperazinylmethyl,(methylsulfonylpiperazinyl)ethyl, or (methylsulfonylpiperazinyl)propyl;and

X, Y, and Z are each independently a nitrogen atom or CH, with theproviso that at least two of X, Y, and Z are nitrogen atoms.

In yet another embodiment, in Formula IA, IB, IC, Ia, Ib, or Ic,

each R¹ is independently hydrogen or —OR^(1a), where R^(1a) is C₁₋₆alkyl, optionally substituted with one or more —NR^(f)R^(g); where R^(f)and R^(g) are each independently hydrogen or C₁₋₆ alkyl;

each R² is independently hydrogen, C₁₋₆ alkyl, or —NR^(1b)R^(1c); whereR^(1b) and R^(1c) are each independently (a) hydrogen; or (b) C₁₋₆alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl, each optionally substituted withone or more substituents, each independently selected from the groupconsisting of —OR^(e) and —NR^(f)R^(g);

each R³ and R⁴ is independently hydrogen or C₁₋₆ alkyl; or R³ and R⁴ arelinked together to form a bond or C₁₋₆ alkylene, optionally substitutedwith one or more substituents;

each R⁵ is independently C₁₋₆ alkyl or C₁₋₆ alkenyl, each optionallysubstituted with one or more substituents, each independently selectedfrom the group consisting of chloro, heterocyclyl, and —NR^(f)R^(g),wherein heterocyclyl is further optionally substituted with one or moresubstituents;

R⁶ is C₁₋₆ alkyl, optionally substituted with one or more halo;

-   -   A, B, D, and E are each independently a bond, C, O, N, S, NH,        CH, or CH₂; wherein the bonds between A, B, D, and E may be        saturated or unsaturated; with the proviso that no more than one        of A, B, D, and E are a bond;

Q is heterocyclylene;

each T¹ is independently a bond, —O—, or —NR⁸—;

each T² is independently a bond or —NR⁸—, with the proviso that the atomthat is attached to —SO₂R⁵ is nitrogen;

each R⁸ is independently (a) hydrogen; or (b) C₁₋₆ alkyl, C₂₋₆ alkenyl,or C₂₋₆ alkynyl, each optionally substituted with one or moresubstituents, each independently selected from the group consisting ofcyano, heterocyclyl, —C(O)R^(e), —C(O)OR^(e), —C(O)NR^(f)R^(g), —OR^(e),—OC(O)R^(e), —OC(O)OR^(e), —OC(O)NR^(f)R^(g), —NR^(f)R^(g),—NR^(e)C(O)R^(h), —NR^(e)C(O)OR^(f), —S(O)₂R^(e), and —S(O)₂NR^(f)R^(g),where heterocyclyl is optionally substituted with one or moresubstituents;

X, Y, and Z are each independently a nitrogen atom or CR⁹, with theproviso that at least two of X, Y, and Z are nitrogen atoms; and

R⁹ is independently hydrogen or C₁₋₆ alkyl.

In yet another embodiment, in Formula IA, IB, IC, Ia, Ib, or Ic,

each R¹ is independently hydrogen, methoxy, or dimethylaminopropoxy;

each R² is independently hydrogen or amino;

R³ and R⁴ are hydrogen; or R³ and R⁴ are linked together to formethylene;

each R⁵ is independently methyl, ethenyl, chloropropyl,dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl,morpholinylmethyl, morpholinylethyl, morpholinylpropyl,(methylpiperazinyl)methyl, (methylpiperazinyl)ethyl,(methylpiperazinyl)propyl, (methylsulfonylpiperazinylmethyl,(methylsulfonylpiperazinyl)ethyl, (methylsulfonylpiperazinyl)propyl,(oxido-thiomorpholinyl)ethyl, or (dioxido-thiomorpholinyl)ethyl;

R⁶ is difluoromethyl;

A, B, D, and E are each independently a bond, C, O, N, S, NH, CH, orCH₂; wherein the bonds between A, B, D, and E may be saturated orunsaturated; with the proviso that no more than one of A, B, D, and Eare a bond;

Q is azetidinylene, cyclopropylene, cyclobutylene, cyclopentylene,cyclohexylene, pyrrolidinylene, pyrrolylene, pyrazolylene,piperidinylene, piperazinylene, phenylene, thiazolylylene, orpyridylene;

each T¹ is independently a bond, —O—, or —NR⁸—;

each T² is independently a bond or —NR⁸—, with the proviso that the atomthat is attached to —SO₂R⁵ is nitrogen;

each R⁸ is independently hydrogen, methyl, ethenyl, chloropropyl,dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl,morpholinylmethyl, morpholinylethyl, morpholinylpropyl,(methylpiperazinyl)methyl, (methylpiperazinyl)ethyl,(methylpiperazinyl)propyl, (methylsulfonylpiperazinylmethyl,(methylsulfonylpiperazinyl)ethyl, or (methylsulfonylpiperazinyl)propyl;and

X, Y, and Z are each independently a nitrogen atom or CH, with theproviso that at least two of X, Y, and Z are nitrogen atoms.

In still another embodiment, Formula IA, IB, IC, Ia, Ib, or Ic,

each R¹ is independently hydrogen, methoxy, or 3-dimethylaminopropoxy;

each R² is independently hydrogen or amino;

R³ and R⁴ are hydrogen; or R³ and R⁴ are linked together to formethylene;

each R⁵ is independently methyl, ethenyl, 3-chloropropyl,dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl,4-morpholinylmethyl, 2-(4-morpholinyl)ethyl, 3-(4-morpholinyl)propyl,(4-methyl-1-piperazinyl)methyl, 2-(4-methyl-1-piperazinyl)ethyl,3-(4-methyl-1-piperazinyl)propyl,4-(methylsulfonyl)-1-piperazinyl-methyl,2-(4-(methylsulfonyl)-1-piperazinyl)ethyl,3-(4-(methylsulfonyl)-1-piperazinyl)propyl,3-(1-oxido-thiomorpholin-4-yl)ethyl, or3-(1,1-dioxido-thiomorpholin-4-yl)ethyl;

R⁶ is difluoromethyl;

A, B, D, and E are each independently a bond, C, O, N, S, NH, CH, orCH₂; wherein the bonds between A, B, D, and E may be saturated orunsaturated; with the proviso that no more than one of A, B, D, and Eare a bond;

Q is 1,3-piperidinylene, 1,4-piperidinylene, or 1,4-piperazinylene;

each T¹ is independently a bond, —O—, or —NR⁸—;

each T² is independently a bond or —NR⁸—, with the proviso that the atomthat is attached to —SO₂R⁵ is nitrogen;

each R⁸ is independently hydrogen, methyl, ethenyl, chloropropyl,dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl,morpholinylmethyl, morpholinylethyl, morpholinylpropyl,(methylpiperazinyl)methyl, (methylpiperazinyl)ethyl,(methylpiperazinyl)propyl, (methylsulfonylpiperazinylmethyl,(methylsulfonylpiperazinyl)ethyl, or (methylsulfonylpiperazinyl)propyl;and

X, Y, and Z are each independently a nitrogen atom or CH, with theproviso that at least two of X, Y, and Z are nitrogen atoms.

In one embodiment, the compound of Formula Ia has the structure ofFormula II:

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof; or a pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof; wherein R¹, R², R³, R⁴, R⁵, R⁶, Q, T¹, andT² are each as defined herein.

In another embodiment, the compound of Formula Ia has the structure ofFormula III:

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof; or a pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof; wherein:

R¹, R², R³, R⁴, R⁵, R⁶, X, Y, and Z are each as defined herein;

T¹ is —O— or —NR⁸—; where R⁸ is hydrogen or C₁₋₆ alkyl, optionallysubstituted with one or more substituents Q¹; and

G and J are each independently a bond, —CH₂—, or —CH₂CH₂—.

In yet another embodiment, the compound of Formula Ia has the structureof Formula III, or an enantiomer, a mixture of enantiomers, or a mixtureof two or more diastereomers thereof; or a pharmaceutically acceptablesalt, solvate, hydrate, or prodrug thereof; wherein:

R¹, R², R³, R⁴, R⁵, R⁶, X, Y, and Z are each as defined herein;

T¹ is a bond, —O—, or —NR⁸—; where R⁸ is hydrogen or C₁₋₆ alkyl,optionally substituted with one or more substituents Q¹; and

G and J are each independently a bond, —CH₂—, or —CH₂CH₂—.

In yet another embodiment, the compound of Formula Ia has the structureof Formula III:

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof; or a pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof; wherein:

R¹, R², R³, R⁴, R⁵, R⁶, X, Y, and Z are each as defined herein;

T¹ is —O— or —NR⁸—; where R⁸ is hydrogen or C₁₋₆ alkyl; and

G and J are each independently a bond, —CH₂—, or —CH₂CH₂—.

In yet another embodiment, the compound of Formula Ia has the structureof Formula III, or an enantiomer, a mixture of enantiomers, or a mixtureof two or more diastereomers thereof; or a pharmaceutically acceptablesalt, solvate, hydrate, or prodrug thereof; wherein:

R¹, R², R³, R⁴, R⁵, R⁶, X, Y, and Z are each as defined herein;

T¹ is a bond, —O—, or —NR⁸—; where R⁸ is hydrogen or C₁₋₆ alkyl; and

G and J are each independently a bond, —CH₂—, or —CH₂CH₂—. In yetanother embodiment, the compound of Formula Ia has the structure ofFormula IV:

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof; or a pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof; wherein:

R¹, R², R³, R⁴, R⁵, R⁶, T², X, Y, and Z are each as defined herein; and

G and J are each independently a bond, —CH₂—, or —CH₂CH₂—.

In yet another embodiment, the compound of Formula Ia has the structureof Formula V:

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof; or a pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof; wherein:

R¹, R², R³, R⁴, R⁵, R⁶, X, Y, and Z are each as defined herein;

G is —CH₂—, or —CH₂CH₂—; and

U is N or CH.

In yet another embodiment, the compound of Formula Ib has the structureof Formula VI:

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof; or a pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof; wherein R¹, R², R³, R⁴, R⁵, R⁶, A, B, D, Q,T¹, and T² are each as defined herein.

In yet another embodiment, the compound of Formula Ic has the structureof Formula VII:

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof; or a pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof; wherein R¹, R², R³, R⁴, R⁵, R⁶, A, B, D, Q,T¹, and T² are each as defined herein.

In still another embodiment, provided here is a compound of FormulaVIII:

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof; or a pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof; wherein:

R¹, R², R³, R⁴, R⁶, G, J, T¹, T², X, Y, and Z are each as definedherein;

R⁵ is C₁₋₆ alkyl, substituted with one or more halo; and

U¹ and U² are each independently N or CH.

In one embodiment, provided herein is a compound of Formula VIII,wherein:

R¹ is —OR^(1a), where R^(1a) is C₁₋₆ alkyl, optionally substituted withone or more substituents as described herein;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁵ is chloromethyl;

R⁶ is C₁₋₆ alkyl, substituted with one or more halo;

G and J are both methylene; or one of them is a bond and the other isethylene;

T¹ is a bond or N(3-dimethylaminopropyl);

T² is a bond, NH, or N(3-dimethylaminopropyl);

U¹ and U² are each independently N or CH; and

X, Y, and Z are N.

In another embodiment, provided herein is a compound of Formula VIII,wherein:

R¹ is methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁵ is chloromethyl;

R⁶ is difluoromethyl;

G and J are both methylene; or G is a bond, and J is ethylene;

T¹ is a bond or N(3-dimethylaminopropyl);

T² is a bond, NH, or N(3-dimethylaminopropyl);

U¹ and U² are each independently N or CH; and

X, Y, and Z are N.

The groups, R¹, R², R³, R⁴, R⁵, R⁶, A, B, D, E, G, J, Q, T¹, T², U, X,Y, and Z in Formulae provided herein, e.g., Formulae IA, IB, IC, Ia, Ib,Ic, II, III, IV, V, VI, VII, and VIII, are further defined in theembodiments described herein. All combinations of the embodimentsprovided herein for such groups are within the scope of this disclosure.

In certain embodiments, each R¹ is independently hydrogen, cyano, halo,or nitro. In certain embodiments, each R¹ is independently C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl, each optionally substituted with one ormore substituents Q¹. In certain embodiments, each R¹ is independently—C(O)R^(1a), —C(O)OR^(1b), —C(O)NR^(1b)R^(1c), or—C(NR^(a))NR^(1b)R^(1c), wherein R^(1a), R^(1b), and R^(1c) are each asdefined herein. In certain embodiments, each R¹ is independently—OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), or —OS(O)₂NR^(1b)R^(1c), wherein R^(1a), R^(1b),and R^(1c) are each as defined herein. In certain embodiments, each R¹is independently —NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d),—NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c);—NR^(1a)C(═NR^(1c))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c), or—NR^(1a)S(O)₂NR^(1b)R^(1c), wherein R^(1a), R^(1b), R^(1c), and R^(1d)are each as defined herein. In certain embodiments, each R¹ isindependently —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c),or —S(O)₂NR^(1b)R^(1c); wherein R^(1a), R^(1b), and R^(1c) are each asdefined herein. In certain embodiments, each R¹ is independentlyhydrogen, methoxy, ethoxy, propoxy, isopropoxy, or dimethylaminopropoxy.In certain embodiments, each R¹ is independently hydrogen, methoxy, or3-dimethylaminopropoxy.

In certain embodiments, each R² is independently hydrogen, cyano, halo,or nitro. In certain embodiments, each R² is independently C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl, each optionally substituted with one ormore substituents Q¹. In certain embodiments, each R² is independently—C(O)R^(1a), —C(O)OR^(1b), —C(O)NR^(1b)R^(1c), orC(NR^(a))NR^(1b)R^(1c), wherein R^(1a), R^(1b), and R^(1c) are each asdefined herein. In certain embodiments, each R² is independently—OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), or —OS(O)₂NR^(1b)R^(1c), wherein R^(1a), R^(1b),and R^(1c) are each as defined herein. In certain embodiments, each R²is independently —NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d),—NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c), or—NR^(1a)S(O)₂NR^(1b)R^(1c), wherein R^(1a), R^(1b), R^(1c), and R^(1d)are each as defined herein. In certain embodiments, each R² isindependently —NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each asdefined herein. In certain embodiments, R² is amino (—NH₂). In certainembodiments, each R² is independently —SR^(1a), —S(O)R^(1a),—S(O)₂R^(1a), —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); whereinR^(1a), R^(1b), and R^(1c) are each as defined herein. In certainembodiments, each R² is independently hydrogen, methoxy, ethoxy,propoxy, isopropoxy, or dimethylaminopropoxy. In certain embodiments, R²is hydrogen.

In certain embodiments, each R³ is independently hydrogen or C₁₋₆ alkyl,optionally substituted with one or more substituents Q¹. In certainembodiments, each R³ is independently hydrogen, methyl, ethyl, or propyl(e.g., n-propyl, isopropyl, or 2-isopropyl). In certain embodiments, R³is hydrogen.

In certain embodiments, each R⁴ is independently hydrogen or C₁₋₆ alkyl,optionally substituted with one or more substituents Q¹. In certainembodiments, each R⁴ is independently hydrogen, methyl, ethyl, or propyl(e.g., n-propyl, isopropyl, or 2-isopropyl). In certain embodiments, R⁴is hydrogen.

In certain embodiments, R³ and R⁴ are linked together to form a bond. Incertain embodiments, R³ and R⁴ are linked together to form C₁₋₆alkylene, optionally substituted with one or more substituents. Incertain embodiments, R³ and R⁴ are linked together to form methylene,ethylene, or propylene, each optionally substituted with one or moresubstituents.

In certain embodiments, each R⁵ is independently C₁₋₆ alkyl, C₂₋₆alkenyl, or C₂₋₆ alkynyl, each optionally substituted with one or moresubstituents Q. In certain embodiments, each R⁵ is independently C₃₋₇cycloalkyl, C₆₋₁₄ aryl, or C₇₋₁₅ aralkyl, each optionally substitutedwith one or more substituents Q¹. In certain embodiments, each R⁵ isindependently heteroaryl or heterocyclyl, each optionally substitutedwith one or more substituents Q¹. In certain embodiments, each R⁵ isindependently C₃₋₇ cycloalkyl-C₁₋₆ alkyl, optionally substituted withone or more substituents. In certain embodiments, each R⁵ isindependently heteroaryl-C₁₋₆ alkyl, optionally substituted with one ormore substituents. In certain embodiments, each R⁵ is independentlyheterocyclyl-C₁₋₆ alkyl, optionally substituted with one or moresubstituents. In certain embodiments, each R⁵ is independently methyl,trifluoromethyl, ethenyl, chloropropyl, dimethylaminomethyl,dimethylaminoethyl, dimethylaminopropyl, pyrrolidinylethyl,morpholinylmethyl, morpholinylmethyl, morpholinylethyl,morpholinylpropyl, piperidinylethyl, methylpiperazinyl,(methylpiperazinyl)methyl, (methylpiperazinyl)ethyl,(hydroxyethyl-piperazinyl)ethyl, (methylpiperazinyl)propyl,(methylsulfonylpiperazinyl)methyl, (methylsulfonylpiperazinyl)ethyl,(methylsulfonylpiperazinyl)propyl, (oxido-thiomorpholinyl)ethyl, or(dioxido-thiomorpholinyl)ethyl, 8-oxa-3-azabicyclo[3.2.1]octanyl-ethyl,(imidazylyl)ethyl, pyridinyl, or (pyridinyl)ethyl. In certainembodiments, each R⁵ is independently methyl, ethenyl, 3-chloropropyl,dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl,2-pyrrolidin-1-yl-ethyl, 4-morpholinylmethyl, 2-(4-morpholinyl)ethyl,3-(4-morpholinyl)propyl, 2-(piperidin-1-yl)ethyl,4-methyl-1-piperazinyl, (4-methyl-1-piperazinyl)methyl,2-(4-methyl-1-piperazinyl)ethyl, 2-(4-hydroxyethyl-1-piperazinyl)ethyl,3-(4-methyl-1-piperazinyl)propyl,4-(methylsulfonyl)-1-piperazinyl-methyl,2-(4-(methylsulfonyl)-1-piperazinyl)ethyl,3-(4-(methylsulfonyl)-1-piperazinyl)propyl,3-oxido-thiomorpholin-4-yl)ethyl,3-(1,1-dioxido-thiomorpholin-4-yl)ethyl,2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)ethyl, 2-(imidazyl-1-yl)-ethyl,3-pyridinyl, 2-(pyridin-2-yl)ethyl, or 2-(pyridin-4-yl)ethyl.

In certain embodiments, each R⁵ is independently C₁₋₆ alkyl, optionallysubstituted with one or more substituents Q. In certain embodiments,each R⁵ is independently C₁₋₆ alkyl, substituted with one or more halogroups. In certain embodiments, each R⁵ is independently C₁₋₆ alkyl,substituted with one or more groups, each of which is independentlyselected from fluoro, chloro, bromo, or iodo. In certain embodiments,each R⁵ is independently chloromethyl. In certain embodiments, each R⁵is independently —(CR^(5a)R^(5b))_(m)—R^(5c), where R^(5a) and R^(5b)are each independently (a) hydrogen, cyano, halo, or nitro; (b) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl; each optionally substituted withone or more substituents; R^(5c) is hydrogen, —NR^(5d)R^(5e), orheterocyclyl; R^(5d) and R^(5e) are each independently hydrogen or C₁₋₆alkyl; and m is an integer of 0, 1, 2, or 3; and where each alkyl andheterocyclyl is independently, optionally substituted with one or moresubstituents as described herein. In certain embodiments, R^(5a) ishydrogen. In certain embodiments, R^(5b) is hydrogen. In certainembodiments, R^(5a) and R^(5b) are hydrogen. In certain embodiments,R^(5c) is hydrogen. In certain embodiments, R^(5c) is —NR^(5d)R^(5e),where R^(5d) and R^(5e) are each independently hydrogen or C₁₋₆ alkyl,optionally substituted with one or more substituents as describedherein. In certain embodiments, R^(5d) is hydrogen or methyl. In certainembodiments, R^(5e) is hydrogen or methyl. In certain embodiments,R^(5c) is amino, methylamino, or dimethylamino. In certain embodiments,R^(5c) is heterocyclyl, optionally substituted with one or moresubstituents as described herein. In certain embodiments, R^(5c) ispyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, each optionallysubstituted with one or more substituents as described herein. Incertain embodiments, R^(5c) is pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, thiomorpholinyl, each optionally substituted with one ormore substituents, wherein each substituent is independently oxo,methyl, or methylsulfonyl. In certain embodiments, R^(5c) is hydrogen,dimethylamino, pyrrolidinyl, methyl-piperazinyl, piperazinyl,hydroxyethyl-piperazinyl, methylsulfonyl-piperazinyl, morpholinyl,oxido-thiomorpholinyl, dioxido-thiomorpholinyl, or8-oxa-3-azabicyclo[3.2.1]octanyl. In certain embodiments, R^(5c) ishydrogen, dimethylamino, pyrrolidin-1-yl, piperazin-1-yl,4-methyl-piperazin-1-yl, 4-(2-hydroxyethyl)-1-piperazinyl,4-methylsulfonyl-1-piperazinyl, 4-morpholinyl,1-oxido-thiomorpholin-4-yl, 1,1-dioxido-thiomorpholin-4-yl, or8-oxa-3-azabicyclo[3.2.1]octan-3-yl. In certain embodiments, m is 1. Incertain embodiments, m is 2.

In certain embodiments, R⁵ is —NR^(5m)R^(5n), where R^(5m) and R^(5n)are each as defined herein. In certain embodiments, R⁵ is(dimethylamino)ethylamino. In certain embodiments, R⁵ is methylamino,dimethylamino, 2-(dimethylamino)ethylamino.

In certain embodiments, R^(5m) is hydrogen. In certain embodiments,R^(5m) is C₁₋₆ alkyl, optionally substituted with one or moresubstituents Q¹. In certain embodiments, R^(5m) is methyl or ethyl,optionally substituted with one or more substituents Q¹. In certainembodiments, R^(5m) is dimethylaminoethyl. In certain embodiments,R^(5m) is 2-dimethylaminoethyl. In certain embodiments, R^(5m) is C₂₋₆alkenyl, optionally substituted with one or more substituents Q¹. Incertain embodiments, R^(5m) is C₂₋₆ alkynyl, optionally substituted withone or more substituents Q¹. In certain embodiments, R^(5m) is C₃₋₇cycloalkyl, optionally substituted with one or more substituents Q¹. Incertain embodiments, R^(5m) is C₆₋₁₄ aryl, optionally substituted withone or more substituents Q¹. In certain embodiments, R^(5m) is C₇₋₁₅aralkyl, optionally substituted with one or more substituents Q¹. Incertain embodiments, R^(5m) is heteroaryl, optionally substituted withone or more substituents Q¹. In certain embodiments, R^(5m) isheterocyclyl, optionally substituted with one or more substituents Q¹.

In certain embodiments, R^(5m) hydrogen. In certain embodiments, R^(5m)is C₁₋₆ alkyl, optionally substituted with one or more substituents Q¹.In certain embodiments, R^(5m) is methyl or ethyl, optionallysubstituted with one or more substituents Q¹. In certain embodiments,R^(5m) is dimethylaminoethyl. In certain embodiments, R^(5m) is2-dimethylaminoethyl. In certain embodiments, R^(5m) is C₂₋₆ alkenyl,optionally substituted with one or more substituents Q¹. In certainembodiments, R^(5m) is C₂₋₆ alkynyl, optionally substituted with one ormore substituents Q¹. In certain embodiments, R^(5m) is C₃₋₇ cycloalkyl,optionally substituted with one or more substituents Q¹. In certainembodiments, R^(5m) is C₆₋₁₄ aryl, optionally substituted with one ormore substituents Q¹. In certain embodiments, R^(5m) is C₇₋₁₅ aralkyl,optionally substituted with one or more substituents Q¹. In certainembodiments, R^(5m) is heteroaryl, optionally substituted with one ormore substituents Q¹. In certain embodiments, R^(5m) is heterocyclyl,optionally substituted with one or more substituents Q¹.

In certain embodiments, R⁶ is hydrogen. In certain embodiments, each R⁶is independently C₁₋₆ alkyl, optionally substituted with one or moresubstituents Q¹. In certain embodiments, each R⁶ is independently C₁₋₆alkyl, optionally substituted with one or more halo. In certainembodiments, each R⁶ is independently C₁₋₆ alkyl, optionally substitutedwith one to three halo. In certain embodiments, each R⁶ is independentlymethyl, fluoromethyl, difluoromethyl, or trifluoromethyl.

In certain embodiments, G is a bond. In certain embodiments, G is —CH₂—.In certain embodiments, G is —CH₂CH₂—.

In certain embodiments, J is a bond. In certain embodiments, J is —CH₂—.In certain embodiments, J is —CH₂CH₂—.

In certain embodiments, G and J are both bonds. In certain embodiments,G and J are both —CH₂—.

In certain embodiments, each Q is independently C₁₋₆ alkylene, C₂₋₆alkenylene, or C₂₋₆ alkynylene, each optionally substituted with one ormore substituents Q¹. In certain embodiments, Q is C₃₋₇ cycloalkylene,optionally substituted with one or more substituents Q¹. In certainembodiments, Q is C₆₋₁₄ arylene, optionally substituted with one or moresubstituents Q¹. In certain embodiments, Q is heteroarylene, optionallysubstituted with one or more substituents Q¹. In certain embodiments, Qis heterocyclylene, optionally substituted with one or more substituentsQ¹. In certain embodiments, Q is cyclopropylene, cyclobutylene,cyclopentylene, cyclohexylene, phenylene, azetidinylene,pyrrolidinylene, piperidinylene, piperazinylene, pyrrolylene,thiazolylylene, pyrazolylene, or pyridylene.

In certain embodiments, T¹ is a bond. In certain embodiments, T¹ is C₁₋₆alkylene, which is optionally substituted with one or more substituentsas described herein. In certain embodiments, T¹ is methylene. In certainembodiments, T¹ is —O—. In certain embodiments, T¹ is —NR⁸—, wherein R⁸is as defined herein. In certain embodiments, T¹ is —NH— or —N(CH₃)—. Incertain embodiments, R⁸ is C₁₋₆ alkyl, optionally substituted with oneor more —NR^(b)R^(c) or heterocyclyl, which is further optionallysubstituted with one or more substituents, wherein R^(b) and R^(c) areeach as defined herein. In certain embodiments, R⁸ is independentlymethyl, ethenyl, chloropropyl, dimethylaminomethyl, dimethylaminoethyl,dimethylaminopropyl, morpholinylmethyl, morpholinylethyl,morpholinylpropyl, (methylpiperazinyl)methyl, (methylpiperazinyl)ethyl,(methylpiperazinyl)propyl, (methylsulfonylpiperazinylmethyl,(methylsulfonylpiperazinyl)-ethyl, or (methylsulfonylpiperazinyl)propyl.In certain embodiments, R⁸ is hydrogen, methyl, dimethylaminopropyl,morpholinyl-propyl, or methylsulfonyl-piperazinyl-propyl. In certainembodiments, R⁸ is hydrogen, methyl, 3-dimethylaminopropyl,3-(4-morpholinyl)propyl, or 3-(4-methylsulfonyl-piperazin-1-yl)propyl.

In certain embodiments, R⁸ of T¹ is independently C₁₋₆ alkyl, optionallysubstituted with one or more substituents as described herein. Incertain embodiments, R⁸ of T¹ is independently—(CR^(8a)R^(8b))_(n)—R^(8c), where R^(8a) and R^(8b) are eachindependently (a) hydrogen, cyano, halo, or nitro; or (b) C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl; each optionally substituted with one ormore substituents Q¹; R^(8c) is hydrogen, —NR^(8d)R^(8e), orheterocyclyl; R^(8d) and R^(8e) are each independently hydrogen or C₁₋₆alkyl; and n is an integer of 0, 1, 2, or 3; and where each alkyl andheterocyclyl is independently, optionally substituted with one or moresubstituents as described herein. In certain embodiments, R^(8a) ishydrogen. In certain embodiments, R^(8b) is hydrogen. In certainembodiments, R^(8a) and R^(8b) are hydrogen. In certain embodiments,R^(8c) is hydrogen. In certain embodiments, R^(8c) is —NR^(8d)R^(8e),where R^(8d) and R^(8e) are each independently hydrogen or C₁₋₆ alkyl,optionally substituted with one or more substituents as describedherein. In certain embodiments, R^(8d) is hydrogen or methyl. In certainembodiments, R^(8e) is hydrogen or methyl. In certain embodiments,R^(8c) is amino, methylamino, or dimethylamino. In certain embodiments,R^(8c) is heterocyclyl, optionally substituted with one or moresubstituents as described herein. In certain embodiments, R^(8c) ispyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, each optionallysubstituted with one or more substituents as described herein. Incertain embodiments, R^(8c) is pyrrolidinyl, piperidinyl, piperazinyl,or morpholinyl, each optionally substituted with one or moresubstituents, wherein each substituent is independently methyl ormethylsulfonyl. In certain embodiments, R^(8c) is hydrogen,dimethylamino, piperazinyl, methylsulfonyl-piperazinyl, or morpholinyl.In certain embodiments, R^(8c) is hydrogen, dimethylamino,piperazin-1-yl, 4-methylsulfonyl-4-piperazinyl, or 4-morpholinyl. Incertain embodiments, n is 1. In certain embodiments, n is 2. In certainembodiments, n is 3.

In certain embodiments, each Q is C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆alkynylene, C₃₋₇ cycloalkylene, C₆₋₁₄ arylene, heteroarylene, orheterocyclylene, each of which is optionally substituted with one ormore substituents as described herein. In certain embodiments, Q is C₁₋₆alkylene, which is optionally substituted with one or more substituentsas described herein. In certain embodiments, Q is C₂₋₆ alkenylene, whichis optionally substituted with one or more substituents as describedherein. In certain embodiments, Q is C₂₋₆ alkynylene, which isoptionally substituted with one or more substituents as describedherein. In certain embodiments, Q is C₃₋₇ cycloalkylene, which isoptionally substituted with one or more substituents as describedherein. In certain embodiments, Q is cyclohexylene, which is optionallysubstituted with one or more substituents as described herein. Incertain embodiments, Q is cis- or trans-cyclohexylene, which isoptionally substituted with one or more substituents as describedherein. In certain embodiments, Q is 1,4-cyclohexylene, which isoptionally substituted with one or more substituents as describedherein. In certain embodiments, Q is cis- or trans-1,4-cyclohexylene,which is optionally substituted with one or more substituents asdescribed herein. In certain embodiments, Q is C₆₋₁₄ arylene, which isoptionally substituted with one or more substituents as describedherein. In certain embodiments, Q is phenylene, which is optionallysubstituted with one or more substituents as described herein. Incertain embodiments, Q is 1,4-phenylene, which is optionally substitutedwith one or more substituents as described herein. In certainembodiments, Q is heteroarylene, which is optionally substituted withone or more substituents as described herein. In certain embodiments, Qis pyridinylene, which is optionally substituted with one or moresubstituents as described herein. In certain embodiments, Q is1,3-pyridinylene, which is optionally substituted with one or moresubstituents as described herein. In certain embodiments, Q isheterocyclylene, which is optionally substituted with one or moresubstituents as described herein. In certain embodiments, Q isazetidinylene, pyrrolidinylene, piperidinylene, or piperazinylene, eachof which is optionally substituted with one or more substituents asdescribed herein. In certain embodiments, Q is azetidinylene,pyrrolidinylene, piperidinylene, or piperazinylene. In certainembodiments, Q is 1,3-azetidinylene, 1,3-pyrrolidinylene,1,3-piperidinylene, 1,4-piperidinylene, or 1,4-piperazinylene, each ofwhich is optionally substituted with one or more substituents asdescribed herein. In certain embodiments, Q is 1,3-piperidinylene,1,4-piperidinylene, or 1,4-piperazinylene.

In certain embodiments, T² is a bond. In certain embodiments, T² is C₁₋₆alkylene, which is optionally substituted with one or more substituentsas described herein. In certain embodiments, T² is methylene. In certainembodiments, T² is —NR⁸—, wherein R⁸ is as defined herein. In certainembodiments, T² is —NH— or —N(CH₃)—. In certain embodiments, R⁸ is C₁₋₆alkyl, optionally substituted with one or more —NR^(b)R^(c) orheterocyclyl, which is further optionally substituted with one or moresubstituents, wherein R^(b) and R^(c) are each as defined herein. Incertain embodiments, R⁸ is independently methyl, ethenyl, chloropropyl,dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl,morpholinylmethyl, morpholinylethyl, morpholinylpropyl,(methylpiperazinyl)methyl, (methylpiperazinyl)ethyl,(methylpiperazinyl)propyl, (methylsulfonylpiperazinylmethyl,(methylsulfonylpiperazinyl)-ethyl, or (methylsulfonylpiperazinyl)propyl.In certain embodiments, R⁸ is hydrogen, methyl, dimethylaminopropyl,morpholinyl-propyl, or methylsulfonyl-piperazinyl-propyl. In certainembodiments, R⁸ is hydrogen, methyl, 3-dimethylaminopropyl,3-(4-morpholinyl)propyl, or 3-(4-methylsulfonyl-piperazin-1-yl)propyl.

In certain embodiments, R⁸ of T² is independently C₁₋₆ alkyl, optionallysubstituted with one or more substituents as described herein. Incertain embodiments, R⁸ of T² is independently—(CR^(8a)R^(8b))_(n)—R^(8c), where R^(8a) and R^(8b) are eachindependently (a) hydrogen, cyano, halo, or nitro; or (b) C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl; each optionally substituted with one ormore substituents Q¹; R^(8c) is hydrogen, —NR^(8d)R^(8e), orheterocyclyl; R^(8d) and R^(8e) are each independently hydrogen or C₁₋₆alkyl; and n is an integer of 0, 1, 2, or 3; and where each alkyl andheterocyclyl is independently, optionally substituted with one or moresubstituents as described herein. In certain embodiments, R^(8a) ishydrogen. In certain embodiments, R^(8b) is hydrogen. In certainembodiments, R^(8a) and R^(8b) are hydrogen. In certain embodiments,R^(8c) is hydrogen. In certain embodiments, R^(8c) is —NR^(8d)R^(8e),where R^(8d) and R^(8e) are each independently hydrogen or C₁₋₆ alkyl,optionally substituted with one or more substituents as describedherein. In certain embodiments, R^(8d) is hydrogen or methyl. In certainembodiments, R^(8e) is hydrogen or methyl. In certain embodiments,R^(8c) is amino, methylamino, or dimethylamino. In certain embodiments,R^(8c) is heterocyclyl, optionally substituted with one or moresubstituents as described herein. In certain embodiments, R^(8c) ispyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, each optionallysubstituted with one or more substituents as described herein. Incertain embodiments, R^(8c) is pyrrolidinyl, piperidinyl, piperazinyl,or morpholinyl, each optionally substituted with one or moresubstituents, wherein each substituent is independently methyl ormethylsulfonyl. In certain embodiments, R^(8c) is hydrogen,dimethylamino, piperazinyl, methylsulfonyl-piperazinyl, or morpholinyl.In certain embodiments, R^(8c) is hydrogen, dimethylamino,piperazin-1-yl, 4-methylsulfonyl-4-piperazinyl, or 4-morpholinyl. Incertain embodiments, n is 1. In certain embodiments, n is 2. In certainembodiments, n is 3.

In certain embodiments, U is N. In certain embodiments, U is CH.

In certain embodiments, X is nitrogen or CR⁹, wherein R⁹ is as definedherein. In certain embodiments, X is nitrogen or CH. In certainembodiments, Y is nitrogen or CR⁹, wherein R⁹ is as defined herein. Incertain embodiments, Y is nitrogen or CH. In certain embodiments, Z isnitrogen or CR⁹, wherein R⁹ is as defined herein. In certainembodiments, Z is nitrogen or CH.

In certain embodiments, X, Y, and Z are nitrogen. In certainembodiments, X and Y are nitrogen, and Z is CH. In certain embodiments,X and Z are nitrogen, and Y is CH. In certain embodiments, Y and Z arenitrogen, and X is CH.

In certain embodiments, each A is independently a bond. In certainembodiments, each A is independently C, N, O, or S. In certainembodiments, each A is independently a nitrogen, oxygen, or sulfur atom.In certain embodiments, each A is independently NR⁷, where R⁷ is asdefined herein. In certain embodiments, each A is independently NH. Incertain embodiments, each A is independently C(O). In certainembodiments, each A is independently CR⁷, where R⁷ is as defined herein.In certain embodiments, each A is independently CR⁷, where R⁷ ishydrogen, halo, or C₁₋₆ alkyl. In certain embodiments, each A isindependently CH. In certain embodiments, each A is independentlyCR⁷R^(7′), where R⁷ and R^(7′) are each as defined herein. In certainembodiments, each A is independently CH₂.

In certain embodiments, each B is independently a bond. In certainembodiments, each B is independently C, N, O, or S. In certainembodiments, each B is independently a nitrogen, oxygen, or sulfur atom.In certain embodiments, each B is independently NR⁷, where R⁷ is asdefined herein. In certain embodiments, each B is independently NH. Incertain embodiments, each B is independently C(O). In certainembodiments, each B is independently CR⁷, where R⁷ is as defined herein.In certain embodiments, each B is independently CR⁷, where R⁷ ishydrogen, halo, or C₁₋₆ alkyl. In certain embodiments, each B isindependently CH. In certain embodiments, each B is independentlyCR⁷R^(7′), where R⁷ and R^(7′) are each as defined herein. In certainembodiments, each B is independently CH₂.

In certain embodiments, each D is independently a bond. In certainembodiments, each D is independently C, N, O, or S. In certainembodiments, each D is independently a nitrogen, oxygen, or sulfur atom.In certain embodiments, each D is independently NR⁷, where R⁷ is asdefined herein. In certain embodiments, each D is independently NH. Incertain embodiments, each D is independently C(O). In certainembodiments, each D is independently CR⁷, where R⁷ is as defined herein.In certain embodiments, each D is independently CR⁷, where R⁷ ishydrogen, halo, or C₁₋₆ alkyl. In certain embodiments, each D isindependently CH. In certain embodiments, each D is independentlyCR⁷R^(7′), where R⁷ and R^(7′) are each as defined herein. In certainembodiments, each D is independently CH₂.

In certain embodiments, each E is independently a bond. In certainembodiments, each E is independently C, N, O, or S. In certainembodiments, each E is independently a nitrogen, oxygen, or sulfur atom.In certain embodiments, each E is independently NR⁷, where R⁷ is asdefined herein. In certain embodiments, each E is independently NH. Incertain embodiments, each E is independently C(O). In certainembodiments, each E is independently CR⁷, where R⁷ is as defined herein.In certain embodiments, each E is independently CR⁷, where R⁷ ishydrogen, halo, or C₁₋₆ alkyl. In certain embodiments, each E isindependently CH. In certain embodiments, each E is independentlyCR⁷R^(7′), where R⁷ and R⁷′ are each as defined herein. In certainembodiments, each E is independently CH₂.

In one embodiment, provided herein is a compound selected from:

-   2-(difluoromethyl)-1-[4-[4-(methylsulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole;-   2-(difluoromethyl)-4-methoxy-1-[4-[4-(methylsulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole;-   2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(vinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole;-   1-[4-{4-[(3-chloropropyl)sulfonyl]-1-piperazinyl}-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole;-   ({4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)-N,N-dimethylmethylamine;-   N-[2-({4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)ethyl]-N,N-dimethylamine;-   N-[3-({4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)propyl]-N,N-dimethylamine;-   2-(difluoromethyl)-4-methoxy-1-(4-(4-morpholinyl)-6-{4-[(4-morpholinylmethyl)sulfonyl]-1-piperazinyl}-1,3,5-triazin-2-yl)-1H-benzimidazole;-   2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[2-(4-morpholinyl)ethyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole;-   2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[3-(4-morpholinyl)propyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole;-   2-(difluoromethyl)-4-methoxy-1-[4-(4-{[(4-methyl-1-piperazinyl)methyl]sulfonyl}-1-piperazinyl)-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole;-   2-(difluoromethyl)-4-methoxy-1-[4-(4-{[2-(4-methyl-1-piperazinyl)ethyl]sulfonyl}-1-piperazinyl)-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-benzimidazole;-   2-(difluoromethyl)-4-methoxy-1-[4-(4-{[3-(4-methyl-1-piperazinyl)propyl]sulfonyl}-1-piperazinyl)-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole;-   2-(difluoromethyl)-4-methoxy-1-[4-[4-({[4-(methylsulfonyl)-1-piperazinyl]methyl}sulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole;-   2-(difluoromethyl)-4-methoxy-1-[4-[4-({2-[4-(methylsulfonyl)-1-piperazinyl]ethyl}sulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole;-   2-(difluoromethyl)-4-methoxy-1-[4-[4-({3-[4-(methylsulfonyl)-1-piperazinyl]propyl}sulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole;-   N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}methanesulfonamide;-   N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}-N-methylmethanesulfonamide;-   N-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N-[1-(methylsulfonyl)-4-piperidinyl]amine;-   N-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N-methyl-N-[1-(methylsulfonyl)-4-piperidinyl]amine;-   2-(difluoromethyl)-4-methoxy-1-[4-[4-(methylsulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazol-6-ylamine;-   2-(difluoromethyl)-4-methoxy-1-[4-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole;-   N-[2-({4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperidinyl}sulfonyl)ethyl]-N,N-dimethylamine;-   2-(difluoromethyl)-4-methoxy-1-[4-[1-(methylsulfonyl)-3-piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole;-   2-(difluoromethyl)-4-methoxyl-[4-{[1-(methylsulfonyl)-4-piperidinyl]oxy}-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole;-   N¹-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N³,N³-dimethyl-N¹-[1-(methylsulfonyl)-3-piperidinyl]-1,3-propanediamine;-   4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[1-(methylsulfonyl)-3-piperidinyl]-6-(4-morpholinyl)-N-[3-(4-morpholinyl)propyl]-1,3,5-triazin-2-amine;-   N¹-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N³,N³-dimethyl-N¹-[1-(methylsulfonyl)-4-piperidinyl]-1,3-propanediamine;-   4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-N-[3-(4-morpholinyl)propyl]-1,3,5-triazin-2-amine;-   4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-{3-[4-(methylsulfonyl)-1-piperazinyl]propyl}-N-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine;-   N-{(3S)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]piperidinyl}-N-[3-(dimethylamino)propyl]methane-sulfonamide;-   N-[2-({4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)ethyl]-N,N-diethylamine;-   2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[2-(1-piperidinyl)ethyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole;-   2-{4-[2-({4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)ethyl]-1-piperazinyl}ethanol;-   2-(difluoromethyl)-1-[4-(4-{[2-(1H-imidazol-1-yl)ethyl]sulfonyl}-1-piperazinyl)-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-methoxy-1H-benzimidazole;-   2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[2-(2-pyridinyl)ethyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole;-   2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[2-(4-pyridinyl)ethyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole;-   2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(3-pyridinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole;-   N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}-2-(dimethylamino)ethanesulfonamide;-   N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}-2-(dimethylamino)-N-methylethanesulfonamide;-   N-{4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]phenyl}-2-(dimethylamino)ethanesulfonamide;-   N-{4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]phenyl}-2-(dimethylamino)-N-methylethanesulfonamide;-   N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-azetidinyl}-2-(dimethylamino)ethanesulfonamide;-   N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-azetidinyl}-2-(dimethylamino)-N-methylethanesulfonamide;-   trans-N-(4-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}cyclohexyl)methanesulfonamide;-   cis-N-(4-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}cyclohexyl)methanesulfonamide;-   N-({1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}methyl)methanesulfonamide;-   N-({1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-piperidinyl}methyl)methanesulfonamide;-   4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-{[1-(methylsulfonyl)-4-piperidinyl]methyl}-6-(4-morpholinyl)-1,3,5-triazin-2-amine;-   N-[2-({4-[4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)ethyl]-N,N-dimethylamine;-   N-[2-({4-[4-[6-amino-2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)ethyl]-N,N-dimethylamine;-   2-(difluoromethyl)-4-methoxy-1-{4-[4-(methylsulfonyl)-1-piperazinyl]-6-tetrahydro-2H-pyran-4-yl-1,3,5-triazin-2-yl}-1H-benzimidazole;-   2-(difluoromethyl)-4-methoxy-1-(4-(4-morpholinyl)-6-{4-[(trifluoromethyl)-sulfonyl]-1-piperazinyl}-1,3,5-triazin-2-yl)-1H-benzimidazole;-   N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}trifluoromethanesulfonamide;-   N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-azetidinyl}(trifluoro)methanesulfonamide;-   4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N,N-dimethyl-1-piperazinesulfonamide;-   1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N,N-dimethyl-4-piperidinesulfonamide;-   1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N-methyl-4-piperidinesulfonamide;-   1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N-[2-(dimethylamino)ethyl]-4-piperidinesulfonamide;-   1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N-methyl-3-pyrrolidinesulfonamide;-   1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N-[2-(dimethylamino)ethyl]-3-pyrrolidinesulfonamide;-   2-(difluoromethyl)-4-methoxy-1-[4-{4-[(4-methyl-1-piperazinyl)sulfonyl]phenyl}-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole;-   N-(5-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}-2-pyridinyl)methanesulfonamide;    and-   N-(5-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}-2-pyridinyl)-N-methylmethanesulfonamide;    and enantiomers, mixtures of enantiomers, or mixtures of two or more    diastereomers thereof; and pharmaceutically acceptable salts,    solvates, hydrates, and prodrugs thereof.

In another embodiment, provided herein is a compound selected from:

-   4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine;-   3-{4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-[4-(methylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-8-oxa-3-azabicyclo[3.2.1]octane;-   2-(difluoromethyl)-4-methoxy-1-[4-[4-(methylsulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-2-pyrimidinyl]-1H-benzimidazole;-   4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[1-(methylsulfonyl)-3-azetidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine;-   4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-methyl-N-[1-(methylsulfonyl)-3-azetidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine;-   N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-azetidinyl}methanesulfonamide;-   N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-azetidinyl}-N-methylmethanesulfonamide;-   4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[(3R)-1-(methylsulfonyl)pyrrolidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine;-   4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-methyl-N-[(3R)-1-(methylsulfonyl)pyrrolidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine;-   4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[(3S)-1-(methylsulfonyl)pyrrolidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine;-   4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-methyl-N-[(3S)-1-(methylsulfonyl)pyrrolidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine;-   N-{(3R)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]pyrrolidinyl}methanesulfonamide;-   N-{(3R)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]pyrrolidinyl}-N-methylmethanesulfonamide;-   N-{(3S)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]pyrrolidinyl}methanesulfonamide;-   N-{(3S)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]pyrrolidinyl}-N-methylmethanesulfonamide;-   4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[(3R)-1-(methylsulfonyl)piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine;-   4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-methyl-N-[(3R)-1-(methylsulfonyl)piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine;-   4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[(3S)-1-(methylsulfonyl)piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine;-   4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-methyl-N-[(3S)-1-(methylsulfonyl)piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine;-   N-{(3R)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]piperidinyl}methanesulfonamide;-   N-{(3R)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]piperidinyl}-N-methylmethanesulfonamide;-   N-{(3S)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]piperidinyl}methanesulfonamide;-   N-{(3S)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]piperidinyl}-N-methylmethanesulfonamide;-   2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[2-(1-oxido-4-thiomorpholinyl)ethyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole;-   2-(difluoromethyl)-1-[4-(4-{[2-(1,1-dioxido-4-thiomorpholinyl)ethyl]sulfonyl}-1-piperazinyl)-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-methoxy-1H-benzimidazole;-   N-{2-[(4-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]oxy}-1-piperidinyl)sulfonyl]ethyl}-N,N-dimethylamine;-   2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[(1-{[2-(4-morpholinyl)ethyl]sulfonyl}-4-piperidinyl)oxy]-1,3,5-triazin-2-yl}-1H-benzimidazole;-   2-(difluoromethyl)-4-methoxy-1-[4-{[1-({2-[4-(methylsulfonyl)-1-piperazinyl]ethyl}sulfonyl)-4-piperidinyl]oxy}-6-(4-morpholinyl)-1,3,5-triazin-2yl]1H-benzimidazole;-   N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}-N-[3-(dimethylamino)propyl]-methanesulfonamide;-   N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}-N-[3-(4-morpholinyl)propyl]-methanesulfonamide;-   2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[2-(1-pyrrolidinyl)ethyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole;    and-   3-[2-({4-[4-[2-(Difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)ethyl]-8-oxa-3-azabicyclo[3.2.1]octane;    and enantiomers, mixtures of enantiomers, or mixtures of two or more    diastereomers thereof; and pharmaceutically acceptable salts,    solvates, hydrates, and prodrugs thereof.

In yet another embodiment, provided herein is a compound selected from:

-   2-(difluoromethyl)-1-[4-(4-morpholinyl)-6-(1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole;-   2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole;-   2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(vinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole;-   N-[3-({2-(difluoromethyl)-1-[4-[4-(methylsulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazol-4-yl}oxy)propyl]-N,N-dimethylamine;-   4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-methyl-N-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine;-   2-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-methyl-N-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-4-pyrimidinamine;-   N-[3-({2-(difluoromethyl)-1-[4-{[1-(methylsulfonyl)-4-piperidinyl]oxy}-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazol-4-yl}oxy)propyl]-N,N-dimethylamine;-   6-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-1-[1-(methylsulfonyl)-4-piperidinyl]-4-(4-morpholinyl)-1H-pyrazolo[3,4-d]pyrimidine;-   2-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-9-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-7,9-dihydro-8H-purin-8-one;-   2-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-9-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-9H-purine;-   5-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-3-[1-(methylsulfonyl)-4-piperidinyl]-7-(4-morpholinyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine;    and-   N-[2-({4-[6-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-4-(4-morpholinyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl}sulfonyl)ethyl]-N,N-dimethylamine;    and enantiomers, mixtures of enantiomers, or mixtures of two or more    diastereomers thereof; and pharmaceutically acceptable salts,    solvates, hydrates, and prodrugs thereof.

In yet another embodiment, provided herein is a compound selected from:

-   N¹-{1-[(chloromethyl)sulfonyl]-4-piperidinyl}-N¹-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N³,N³-dimethyl-1,3-propanediamine;-   chloro-N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}-N-[3-(dimethylamino)propyl]methanesulfonamide;-   chloro-N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}methanesulfonamide;    and-   chloro-N-{(3S)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-piperidinyl}methanesulfonamide;    and enantiomers, mixtures of enantiomers, or mixtures of two or more    diastereomers thereof; and pharmaceutically acceptable salts,    solvates, hydrates, and prodrugs thereof.

The compounds provided herein are intended to encompass all possiblestereoisomers, unless a particular stereochemistry is specified. Wherethe compound provided herein contains an alkenyl or alkenylene group,the compound may exist as one or mixture of geometric cis/trans (or Z/E)isomers. Where structural isomers are interconvertible, the compound mayexist as a single tautomer or a mixture of tautomers. This can take theform of proton tautomerism in the compound that contains, for example,an imino, keto, or oxime group; or so-called valence tautomerism in thecompound that contain an aromatic moiety. It follows that a singlecompound may exhibit more than one type of isomerism.

The compounds provided herein may be enantiomerically pure, such as asingle enantiomer or a single diastereomer, or be stereoisomericmixtures, such as a mixture of enantiomers, e.g., a racemic mixture oftwo enantiomers; or a mixture of two or more diastereomers. As such, oneof skill in the art will recognize that administration of a compound inits (R) form is equivalent, for compounds that undergo epimerization invivo, to administration of the compound in its (S) form. Conventionaltechniques for the preparation/isolation of individual enantiomersinclude synthesis from a suitable optically pure precursor, asymmetricsynthesis from achiral starting materials, or resolution of anenantiomeric mixture, for example, chiral chromatography,recrystallization, resolution, diastereomeric salt formation, orderivatization into diastereomeric adducts followed by separation.

When the compound provided herein contains an acidic or basic moiety, itmay also be provided as a pharmaceutically acceptable salt (See, Bergeet al., J. Pharm. Sci. 1977, 66, 1-19; and “Handbook of PharmaceuticalSalts, Properties, and Use,” Stahl and Wermuth, Ed.; Wiley-VCH and VHCA,Zurich, 2002).

Suitable acids for use in the preparation of pharmaceutically acceptablesalts include, but are not limited to, acetic acid, 2,2-dichloroaceticacid, acylated amino acids, adipic acid, alginic acid, ascorbic acid,L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoicacid, boric acid, (+)-camphoric acid, camphorsulfonic acid,(+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylicacid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamicacid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonicacid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid,galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid,D-glucuronic acid, L-glutamic acid, α-oxoglutaric acid, glycolic acid,hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid,(+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, lauric acid,maleic acid, (−)-L-malic acid, malonic acid, (±)-DL-mandelic acid,methanesulfonic acid, naphthalene-2-sulfonic acid,naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinicacid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid,pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid,saccharic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid,stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaricacid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, andvaleric acid.

Suitable bases for use in the preparation of pharmaceutically acceptablesalts, including, but not limited to, inorganic bases, such as magnesiumhydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, orsodium hydroxide; and organic bases, such as primary, secondary,tertiary, and quaternary, aliphatic and aromatic amines, includingL-arginine, benethamine, benzathine, choline, deanol, diethanolamine,diethylamine, dimethylamine, dipropylamine, diisopropylamine,2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine,isopropylamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine,morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine,piperazine, propylamine, pyrrolidine, 1-(2-hydroxyethyl)-pyrrolidine,pyridine, quinuclidine, quinoline, isoquinoline, secondary amines,triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine,2-amino-2-(hydroxymethyl)-1,3-propanediol, and tromethamine.

In certain embodiments, the compounds provided herein arepharmacologically acceptable salts of the compounds with one or more ofhydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic,salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic,and isoethonic acids; or with one or more of potassium carbonate, sodiumor potassium hydroxide, ammonia, triethylamine, and triethanolamine.

The compound provided herein may also be provided as a prodrug, which isa functional derivative of the compound, for example, of Formula I andis readily convertible into the parent compound in vivo. Prodrugs areoften useful because, in some situations, they may be easier toadminister than the parent compound. They may, for instance, bebioavailable by oral administration whereas the parent compound is not.The prodrug may also have enhanced solubility in pharmaceuticalcompositions over the parent compound. A prodrug may be converted intothe parent drug by various mechanisms, including enzymatic processes andmetabolic hydrolysis. See Harper, Progress in Drug Research 1962, 4,221-294; Morozowich et al. in “Design of Biopharmaceutical Propertiesthrough Prodrugs and Analogs,” Roche Ed., APHA Acad. Pharm. Sci. 1977;“Bioreversible Carriers in Drug in Drug Design, Theory and Application,”Roche Ed., APHA Acad. Pharm. Sci. 1987; “Design of Prodrugs,” Bundgaard,Elsevier, 1985; Wang et al., Curr. Pharm. Design 1999, 5, 265-287;Pauletti et al., Adv. Drug. Delivery Rev. 1997, 27, 235-256; Mizen etal., Pharm. Biotech. 1998, 11, 345-365; Gaignault et al., Pract. Med.Chem. 1996, 671-696; Asgharnejad in “Transport Processes inPharmaceutical Systems,” Amidon et al., Ed., Marcell Dekker, 185-218,2000; Balant et al., Eur. J. Drug Metab. Pharmacokinet. 1990, 15,143-53; Balimane and Sinko, Adv. Drug Delivery Rev. 1999, 39, 183-209;Browne, Clin. Neuropharmacol. 1997, 20, 1-12; Bundgaard, Arch. Pharm.Chem. 1979, 86, 1-39; Bundgaard, Controlled Drug Delivery 1987, 17,179-96; Bundgaard, Adv. Drug Delivery Rev. 1992, 8, 1-38; Fleisher etal., Adv. Drug Delivery Rev. 1996, 19, 115-130; Fleisher et al., MethodsEnzymol. 1985, 112, 360-381; Farquhar et al., J. Pharm. Sci. 1983, 72,324-325; Freeman et al., J. Chem. Soc., Chem. Commun. 1991, 875-877;Friis and Bundgaard, Eur. J. Pharm. Sci. 1996, 4, 49-59; Gangwar et al.,Des. Biopharm. Prop. Prodrugs Analogs, 1977, 409-421; Nathwani and Wood,Drugs 1993, 45, 866-94; Sinhababu and Thakker, Adv. Drug Delivery Rev.1996, 19, 241-273; Stella et al., Drugs 1985, 29, 455-73; Tan et al.,Adv. Drug Delivery Rev. 1999, 39, 117-151; Taylor, Adv. Drug DeliveryRev. 1996, 19, 131-148; Valentino and Borchardt, Drug Discovery Today1997, 2, 148-155; Wiebe and Knaus, Adv. Drug Delivery Rev. 1999, 39,63-80; and Waller et al., Br. J. Clin. Pharmac. 1989, 28, 497-507.

In certain embodiments, the compounds provided herein are reversibleinhibitors of PI3K. In certain embodiments, the compounds providedherein are irreversible inhibitors of PI3K. In certain embodiments, thecompounds provided herein are selective reversible inhibitors of PI3Kisoforms. In certain embodiments, the compounds provided herein areselective irreversible inhibitors of PI3K isoforms.

In certain embodiments, the compounds provided herein are reversibleinhibitors of p110α. In certain embodiments, the compounds providedherein are irreversible inhibitors of p110α. In certain embodiments, thecompounds provided herein are selective reversible inhibitors of p110α.In certain embodiments, the compounds provided herein are selectiveirreversible inhibitors of p110α.

Without being bound by any theory, it is believed that, in certainembodiments, the compounds provided herein interact with the His-855,which is unique to p110α. Without being bound by any theory, it isbelieved that, in certain embodiments, the compounds provided hereinreact with the His-855, which is unique to p110α. Without being bound byany theory, it is believed that, in certain embodiments, the compoundsprovided herein alkylate the His-855, which is unique to p110α.

Without being bound by any theory, it is believed that, in certainembodiments, the compounds provided herein are adapted to irreversiblyinhibit the p110α isoform of PI3K. Without being bound by any theory, itis believed that, in certain embodiments, the compounds provided hereinare adapted to target the His-855 group which is considered to form partof the ATP binding pocket of the p110α isoform of PI3K, but not of theother isoforms. Without being bound by any theory, it is believed that,in certain embodiments, by targeting the His-855 of p110α, the compoundsprovided herein selectively and irreversibly inhibit this PI3K isoform.

Irreversible inhibition of an enzyme target has a number of potentialadvantages: e.g., (a) kinase inhibitors that shut down the ATP site byreversible competitive blockade of ATP have to bind very tightly to theenzyme and/or maintain high plasma levels for prolonged periods, inorder to compete with ATP binding, since ATP levels in cells are high;(b) the enzyme is shut down permanently, and the pathway is onlyreactivated upon resynthesis of the enzyme, which may take some time;(c) it allows longer times between doses, for a more achievable dosageregime; (d) it provides an additional mechanism for selectivity, in oneembodiment, between different isoforms of an enzyme.

In certain embodiments, the sulfonamide compounds provided hereinexhibit greater pharmacological stability than the correspondingcarboxamides. In certain embodiments, the sulfonamide compounds providedherein exhibit an increase of no less than 2-fold, 3-fold, 4-fold, or5-fold in pharmacological stability than the corresponding carboxamides.In certain embodiments, the sulfonamide compounds provided hereinexhibit greater stability in human plasma than the correspondingcarboxamides. In certain embodiments, the sulfonamide compounds providedherein exhibit an increase of no less than 2-fold, 3-fold, 4-fold, or5-fold in stability in human plasma than the corresponding carboxamides.

Methods of Synthesis

The compound provided herein can be prepared, isolated, or obtained byany method known to one of skill in the art, and the following examplesare only representative and do not exclude other related procedures.

For example, the compounds of Formula Ia, Ib, or Ic can be prepared viathe formation of a bond between the T² and SO₂R⁵ groups (Method A) asshown in Scheme 1.

The compounds of Formula Ia, Ib, or Ic can also be prepared via theformation of a bond between the benzimidazole group and the pyrimidinylor 1,3,5-triazilnyl ring (Method B) as shown in Scheme 2.

Furthermore, the compounds of Formula Ia can be prepared via theformation of a bond between Q and the pyrimidinyl or 1,3,5-triazinylring (Method C) as shown in Scheme 3.

The halo-1,3,5-triazine or halo-pyrimidine used in Method C can beprepared, isolated, or obtained by any method known to one of skill inthe art. For example, the halo-1,3,5-triazine 1 can be prepared viaaromatic substitution reactions of chlorotriazine with two differentamines as shown in Scheme 4.

The benzimidazole 4 used in Scheme 4 can also be prepared, isolated, orobtained by any method known to one of skill in the art. For example,the benzimidazole 4 can be as shown in Scheme 5.

The compounds of Formula Ia, Ib, or Ic can also be prepared via themodification of existing substituents on the compounds (Method D).

Pharmaceutical Compositions

In one embodiment, provided herein is a pharmaceutical compositioncomprising a compound of Formula IA, IB, or IC as defined herein, and apharmaceutically acceptable excipient, adjuvant, carrier, buffer, orstabiliser.

In one embodiment, the pharmaceutically acceptable excipient, adjuvant,carrier, buffer, or stabiliser is non-toxic and does not interfere withthe efficacy of the active ingredient. The precise nature of the carrieror other material will depend on the route of administration, which maybe oral or by injection, such as cutaneous, subcutaneous, or intravenousinjection.

In one embodiment, the pharmaceutical compositions are provided in adosage form for oral administration, which comprise a compound providedherein, and one or more pharmaceutically acceptable excipients orcarriers. The pharmaceutical compositions provided herein that areformulated for oral administration may be in tablet, capsule, powder, orliquid form. A tablet may comprise a solid carrier or an adjuvant.Liquid pharmaceutical compositions generally comprise a liquid carriersuch as water, petroleum, animal or vegetable oils, or mineral oil orsynthetic oil. Physiological saline solution, dextrose or othersaccharide solution, or glycols such as ethylene glycol, propyleneglycol, or polyethylene glycol may be included. A capsule may comprise asolid carrier such as gelatin.

In another embodiment, the pharmaceutical compositions are provided in adosage form for parenteral administration, and one or morepharmaceutically acceptable excipients or carriers. Where pharmaceuticalcompositions may be formulated for intravenous, cutaneous orsubcutaneous injection, the active ingredient will be in the form of aparenterally acceptable aqueous solution, which is pyrogen-free and hasa suitable pH, isotonicity, and stability. Those of relevant skill inthe art are well able to prepare suitable solutions using, for example,isotonic vehicles, such as Sodium Chloride injection, Ringer'sinjection, or Lactated Ringer's injection. Preservatives, stabilisers,buffers, antioxidants, and/or other additives may be included asrequired.

In yet another embodiment, the pharmaceutical compositions are providedin a dosage form for topical administration, which comprise a compoundprovided herein, and one or more pharmaceutically acceptable excipientsor carriers.

The pharmaceutical compositions can also be formulated as modifiedrelease dosage forms, including delayed-, extended-, prolonged-,sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-,programmed-release, and gastric retention dosage forms. These dosageforms can be prepared according to conventional methods and techniquesknown to those skilled in the art (see, Remington: The Science andPractice of Pharmacy, supra; Modified-Release Drug Delivery Technology,2nd Edition, Rathbone et al., Eds., Marcel Dekker, Inc.: New York, N.Y.,2008).

The pharmaceutical compositions provided herein can be provided in aunit-dosage form or multiple-dosage form. A unit-dosage form, as usedherein, refers to physically discrete a unit suitable for administrationto a human and animal subject, and packaged individually as is known inthe art. Each unit-dose contains a predetermined quantity of an activeingredient(s) sufficient to produce the desired therapeutic effect, inassociation with the required pharmaceutical carriers or excipients.Examples of a unit-dosage form include an ampoule, syringe, andindividually packaged tablet and capsule. A unit-dosage form may beadministered in fractions or multiples thereof. A multiple-dosage formis a plurality of identical unit-dosage forms packaged in a singlecontainer to be administered in segregated unit-dosage form. Examples ofa multiple-dosage form include a vial, bottle of tablets or capsules, orbottle of pints or gallons.

The pharmaceutical compositions provided herein can be administered atonce, or multiple times at intervals of time. It is understood that theprecise dosage and duration of treatment may vary with the age, weight,and condition of the patient being treated, and may be determinedempirically using known testing protocols or by extrapolation from invivo or in vitro test or diagnostic data. It is further understood thatfor any particular individual, specific dosage regimens should beadjusted over time according to the individual need and the professionaljudgment of the person administering or supervising the administrationof the formulations.

In another embodiment, the pharmaceutical compositions provided hereinfurther comprise one or more chemotherapeutic agents as defined herein.

In yet another embodiment, provided herein is the use of a compound ofFormula IA, IB, or IC in the manufacture of a medicament for thetreatment of cancer. In certain embodiments, the medicament is intablet, capsule, powder, or liquid form. In certain embodiments, themedicament is formulated as described herein.

A. Oral Administration

The pharmaceutical compositions provided herein for oral administrationcan be provided in solid, semisolid, or liquid dosage forms for oraladministration. As used herein, oral administration also includesbuccal, lingual, and sublingual administration. Suitable oral dosageforms include, but are not limited to, tablets, fastmelts, chewabletablets, capsules, pills, strips, troches, lozenges, pastilles, cachets,pellets, medicated chewing gum, bulk powders, effervescent ornon-effervescent powders or granules, oral mists, solutions, emulsions,suspensions, wafers, sprinkles, elixirs, and syrups. In addition to theactive ingredient(s), the pharmaceutical compositions can contain one ormore pharmaceutically acceptable carriers or excipients, including, butnot limited to, binders, fillers, diluents, disintegrants, wettingagents, lubricants, glidants, coloring agents, dye-migration inhibitors,sweetening agents, flavoring agents, emulsifying agents, suspending anddispersing agents, preservatives, solvents, non-aqueous liquids, organicacids, and sources of carbon dioxide.

Binders or granulators impart cohesiveness to a tablet to ensure thetablet remaining intact after compression. Suitable binders orgranulators include, but are not limited to, starches, such as cornstarch, potato starch, and pre-gelatinized starch (e.g., STARCH 1500);gelatin; sugars, such as sucrose, glucose, dextrose, molasses, andlactose; natural and synthetic gums, such as acacia, alginic acid,alginates, extract of Irish moss, panwar gum, ghatti gum, mucilage ofisabgol husks, carboxymethylcellulose, methylcellulose,polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, powderedtragacanth, and guar gum; celluloses, such as ethyl cellulose, celluloseacetate, carboxymethyl cellulose calcium, sodium carboxymethylcellulose, methyl cellulose, hydroxyethylcellulose (HEC),hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPMC);microcrystalline celluloses, such as AVICEL-PH-101, AVICEL-PH-103,AVICEL RC-581, AVICEL-PH-105 (FMC Corp., Marcus Hook, Pa.); and mixturesthereof. Suitable fillers include, but are not limited to, talc, calciumcarbonate, microcrystalline cellulose, powdered cellulose, dextrates,kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinizedstarch, and mixtures thereof. The amount of a binder or filler in thepharmaceutical compositions provided herein varies upon the type offormulation, and is readily discernible to those of ordinary skill inthe art. The binder or filler may be present from about 50 to about 99%by weight in the pharmaceutical compositions provided herein.

Suitable diluents include, but are not limited to, dicalcium phosphate,calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose,kaolin, mannitol, sodium chloride, dry starch, and powdered sugar.Certain diluents, such as mannitol, lactose, sorbitol, sucrose, andinositol, when present in sufficient quantity, can impart properties tosome compressed tablets that permit disintegration in the mouth bychewing. Such compressed tablets can be used as chewable tablets. Theamount of a diluent in the pharmaceutical compositions provided hereinvaries upon the type of formulation, and is readily discernible to thoseof ordinary skill in the art.

Suitable disintegrants include, but are not limited to, agar; bentonite;celluloses, such as methylcellulose and carboxymethylcellulose; woodproducts; natural sponge; cation-exchange resins; alginic acid; gums,such as guar gum and Veegum HV; citrus pulp; cross-linked celluloses,such as croscarmellose; cross-linked polymers, such as crospovidone;cross-linked starches; calcium carbonate; microcrystalline cellulose,such as sodium starch glycolate; polacrilin potassium; starches, such ascorn starch, potato starch, tapioca starch, and pre-gelatinized starch;clays; aligns; and mixtures thereof. The amount of a disintegrant in thepharmaceutical compositions provided herein varies upon the type offormulation, and is readily discernible to those of ordinary skill inthe art. The amount of a disintegrant in the pharmaceutical compositionsprovided herein varies upon the type of formulation, and is readilydiscernible to those of ordinary skill in the art. The pharmaceuticalcompositions provided herein may contain from about 0.5 to about 15% orfrom about 1 to about 5% by weight of a disintegrant.

Suitable lubricants include, but are not limited to, calcium stearate;magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol;mannitol; glycols, such as glycerol behenate and polyethylene glycol(PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetableoil, including peanut oil, cottonseed oil, sunflower oil, sesame oil,olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyllaureate; agar; starch; lycopodium; silica or silica gels, such asAEROSIL® 200 (W.R. Grace Co., Baltimore, Md.) and CAB-O-SIL® (Cabot Co.of Boston, Mass.); and mixtures thereof. The pharmaceutical compositionsprovided herein may contain about 0.1 to about 5% by weight of alubricant.

Suitable glidants include, but are not limited to, colloidal silicondioxide, CAB-O-SIL® (Cabot Co. of Boston, Mass.), and asbestos-freetalc. Suitable coloring agents include, but are not limited to, any ofthe approved, certified, water soluble FD&C dyes, and water insolubleFD&C dyes suspended on alumina hydrate, and color lakes and mixturesthereof. A color lake is the combination by adsorption of awater-soluble dye to a hydrous oxide of a heavy metal, resulting in aninsoluble form of the dye. Suitable flavoring agents include, but arenot limited to, natural flavors extracted from plants, such as fruits,and synthetic blends of compounds which produce a pleasant tastesensation, such as peppermint and methyl salicylate. Suitable sweeteningagents include, but are not limited to, sucrose, lactose, mannitol,syrups, glycerin, and artificial sweeteners, such as saccharin andaspartame. Suitable emulsifying agents include, but are not limited to,gelatin, acacia, tragacanth, bentonite, and surfactants, such aspolyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylenesorbitan monooleate 80 (TWEEN® 80), and triethanolamine oleate. Suitablesuspending and dispersing agents include, but are not limited to, sodiumcarboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodiumcarbomethylcellulose, hydroxypropyl methylcellulose, andpolyvinylpyrrolidone. Suitable preservatives include, but are notlimited to, glycerin, methyl and propylparaben, benzoic add, sodiumbenzoate and alcohol. Suitable wetting agents include, but are notlimited to, propylene glycol monostearate, sorbitan monooleate,diethylene glycol monolaurate, and polyoxyethylene lauryl ether.Suitable solvents include, but are not limited to, glycerin, sorbitol,ethyl alcohol, and syrup. Suitable non-aqueous liquids utilized inemulsions include, but are not limited to, mineral oil and cottonseedoil. Suitable organic acids include, but are not limited to, citric andtartaric acid. Suitable sources of carbon dioxide include, but are notlimited to, sodium bicarbonate and sodium carbonate.

It should be understood that many carriers and excipients may serveseveral functions, even within the same formulation.

The pharmaceutical compositions provided herein for oral administrationcan be provided as compressed tablets, tablet triturates, chewablelozenges, rapidly dissolving tablets, multiple compressed tablets, orenteric-coating tablets, sugar-coated, or film-coated tablets.Enteric-coated tablets are compressed tablets coated with substancesthat resist the action of stomach acid but dissolve or disintegrate inthe intestine, thus protecting the active ingredients from the acidicenvironment of the stomach. Enteric-coatings include, but are notlimited to, fatty acids, fats, phenyl salicylate, waxes, shellac,ammoniated shellac, and cellulose acetate phthalates. Sugar-coatedtablets are compressed tablets surrounded by a sugar coating, which maybe beneficial in covering up objectionable tastes or odors and inprotecting the tablets from oxidation. Film-coated tablets arecompressed tablets that are covered with a thin layer or film of awater-soluble material. Film coatings include, but are not limited to,hydroxyethylcellulose, sodium carboxymethylcellulose, polyethyleneglycol 4000, and cellulose acetate phthalate. Film coating imparts thesame general characteristics as sugar coating. Multiple compressedtablets are compressed tablets made by more than one compression cycle,including layered tablets, and press-coated or dry-coated tablets.

The tablet dosage forms can be prepared from the active ingredient inpowdered, crystalline, or granular forms, alone or in combination withone or more carriers or excipients described herein, including binders,disintegrants, controlled-release polymers, lubricants, diluents, and/orcolorants. Flavoring and sweetening agents are especially useful in theformation of chewable tablets and lozenges.

The pharmaceutical compositions provided herein for oral administrationcan be provided as soft or hard capsules, which can be made fromgelatin, methylcellulose, starch, or calcium alginate. The hard gelatincapsule, also known as the dry-filled capsule (DFC), consists of twosections, one slipping over the other, thus completely enclosing theactive ingredient. The soft elastic capsule (SEC) is a soft, globularshell, such as a gelatin shell, which is plasticized by the addition ofglycerin, sorbitol, or a similar polyol. The soft gelatin shells maycontain a preservative to prevent the growth of microorganisms. Suitablepreservatives are those as described herein, including methyl- andpropyl-parabens, and sorbic acid. The liquid, semisolid, and soliddosage forms provided herein may be encapsulated in a capsule. Suitableliquid and semisolid dosage forms include solutions and suspensions inpropylene carbonate, vegetable oils, or triglycerides. Capsulescontaining such solutions can be prepared as described in U.S. Pat. Nos.4,328,245; 4,409,239; and 4,410,545. The capsules may also be coated asknown by those of skill in the art in order to modify or sustaindissolution of the active ingredient.

The pharmaceutical compositions provided herein for oral administrationcan be provided in liquid and semisolid dosage forms, includingemulsions, solutions, suspensions, elixirs, and syrups. An emulsion is atwo-phase system, in which one liquid is dispersed in the form of smallglobules throughout another liquid, which can be oil-in-water orwater-in-oil. Emulsions may include a pharmaceutically acceptablenon-aqueous liquid or solvent, emulsifying agent, and preservative.Suspensions may include a pharmaceutically acceptable suspending agentand preservative. Aqueous alcoholic solutions may include apharmaceutically acceptable acetal, such as a di(lower alkyl) acetal ofa lower alkyl aldehyde, e.g., acetaldehyde diethyl acetal; and awater-miscible solvent having one or more hydroxyl groups, such aspropylene glycol and ethanol. Elixirs are clear, sweetened, andhydroalcoholic solutions. Syrups are concentrated aqueous solutions of asugar, for example, sucrose, and may also contain a preservative. For aliquid dosage form, for example, a solution in a polyethylene glycol maybe diluted with a sufficient quantity of a pharmaceutically acceptableliquid carrier, e.g., water, to be measured conveniently foradministration.

Other useful liquid and semisolid dosage forms include, but are notlimited to, those containing the active ingredient(s) provided herein,and a dialkylated mono- or poly-alkylene glycol, including,1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethyleneglycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether,polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 referto the approximate average molecular weight of the polyethylene glycol.These formulations can further comprise one or more antioxidants, suchas butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA),propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine,lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoricacid, bisulfite, sodium metabisulfite, thiodipropionic acid and itsesters, and dithiocarbamates.

The pharmaceutical compositions provided herein for oral administrationcan be also provided in the forms of liposomes, micelles, microspheres,or nanosystems. Micellar dosage forms can be prepared as described inU.S. Pat. No. 6,350,458.

The pharmaceutical compositions provided herein for oral administrationcan be provided as non-effervescent or effervescent, granules andpowders, to be reconstituted into a liquid dosage form. Pharmaceuticallyacceptable carriers and excipients used in the non-effervescent granulesor powders may include diluents, sweeteners, and wetting agents.Pharmaceutically acceptable carriers and excipients used in theeffervescent granules or powders may include organic acids and a sourceof carbon dioxide.

Coloring and flavoring agents can be used in all of the above dosageforms.

The pharmaceutical compositions provided herein for oral administrationcan be formulated as immediate or modified release dosage forms,including delayed-, sustained, pulsed-, controlled, targeted-, andprogrammed-release forms.

B. Parenteral Administration

The pharmaceutical compositions provided herein can be administeredparenterally by injection, infusion, or implantation, for local orsystemic administration. Parenteral administration, as used herein,include intravenous, intraarterial, intraperitoneal, intrathecal,intraventricular, intraurethral, intrasternal, intracranial,intramuscular, intrasynovial, intravesical, and subcutaneousadministration.

The pharmaceutical compositions provided herein for parenteraladministration can be formulated in any dosage forms that are suitablefor parenteral administration, including solutions, suspensions,emulsions, micelles, liposomes, microspheres, nanosystems, and solidforms suitable for solutions or suspensions in liquid prior toinjection. Such dosage forms can be prepared according to conventionalmethods known to those skilled in the art of pharmaceutical science(see, Remington: The Science and Practice of Pharmacy, supra).

The pharmaceutical compositions intended for parenteral administrationcan include one or more pharmaceutically acceptable carriers andexcipients, including, but not limited to, aqueous vehicles,water-miscible vehicles, non-aqueous vehicles, antimicrobial agents orpreservatives against the growth of microorganisms, stabilizers,solubility enhancers, isotonic agents, buffering agents, antioxidants,local anesthetics, suspending and dispersing agents, wetting oremulsifying agents, complexing agents, sequestering or chelating agents,cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents,and inert gases.

Suitable aqueous vehicles include, but are not limited to, water,saline, physiological saline or phosphate buffered saline (PBS), sodiumchloride injection, Ringers injection, isotonic dextrose injection,sterile water injection, dextrose and lactated Ringers injection.Suitable non-aqueous vehicles include, but are not limited to, fixedoils of vegetable origin, castor oil, corn oil, cottonseed oil, oliveoil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil,hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chaintriglycerides of coconut oil, and palm seed oil. Suitable water-misciblevehicles include, but are not limited to, ethanol, 1,3-butanediol,liquid polyethylene glycol (e.g., polyethylene glycol 300 andpolyethylene glycol 400), propylene glycol, glycerin,N-methyl-2-pyrrolidone, N,N-dimethylacetamide, and dimethyl sulfoxide.

Suitable antimicrobial agents or preservatives include, but are notlimited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol,methyl and propyl p-hydroxybenzoates, thimerosal, benzalkonium chloride(e.g., benzethonium chloride), methyl- and propyl-parabens, and sorbicacid. Suitable isotonic agents include, but are not limited to, sodiumchloride, glycerin, and dextrose. Suitable buffering agents include, butare not limited to, phosphate and citrate. Suitable antioxidants arethose as described herein, including bisulfite and sodium metabisulfite.Suitable local anesthetics include, but are not limited to, procainehydrochloride. Suitable suspending and dispersing agents are those asdescribed herein, including sodium carboxymethylcelluose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agentsare those described herein, including polyoxyethylene sorbitanmonolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamineoleate. Suitable sequestering or chelating agents include, but are notlimited to EDTA. Suitable pH adjusting agents include, but are notlimited to, sodium hydroxide, hydrochloric acid, citric acid, and lacticacid. Suitable complexing agents include, but are not limited to,cyclodextrins, including α-cyclodextrin, β-cyclodextrin,hydroxypropyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin, andsulfobutylether 7-β-cyclodextrin (CAPTISOL®, CyDex, Lenexa, Kans.).

When the pharmaceutical compositions provided herein are formulated formultiple dosage administration, the multiple dosage parenteralformulations must contain an antimicrobial agent at bacteriostatic orfungistatic concentrations. All parenteral formulations must be sterile,as known and practiced in the art.

In one embodiment, the pharmaceutical compositions for parenteraladministration are provided as ready-to-use sterile solutions. Inanother embodiment, the pharmaceutical compositions are provided assterile dry soluble products, including lyophilized powders andhypodermic tablets, to be reconstituted with a vehicle prior to use. Inyet another embodiment, the pharmaceutical compositions are provided asready-to-use sterile suspensions. In yet another embodiment, thepharmaceutical compositions are provided as sterile dry insolubleproducts to be reconstituted with a vehicle prior to use. In stillanother embodiment, the pharmaceutical compositions are provided asready-to-use sterile emulsions.

The pharmaceutical compositions provided herein for parenteraladministration can be formulated as immediate or modified release dosageforms, including delayed-, sustained, pulsed-, controlled, targeted-,and programmed-release forms.

The pharmaceutical compositions provided herein for parenteraladministration can be formulated as a suspension, solid, semi-solid, orthixotropic liquid, for administration as an implanted depot. In oneembodiment, the pharmaceutical compositions provided herein aredispersed in a solid inner matrix, which is surrounded by an outerpolymeric membrane that is insoluble in body fluids but allows theactive ingredient in the pharmaceutical compositions diffuse through.

Suitable inner matrixes include, but are not limited to,polymethylmethacrylate, polybutyl-methacrylate, plasticized orunplasticized polyvinylchloride, plasticized nylon, plasticizedpolyethylene terephthalate, natural rubber, polyisoprene,polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetatecopolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonatecopolymers, hydrophilic polymers, such as hydrogels of esters of acrylicand methacrylic acid, collagen, cross-linked polyvinyl alcohol, andcross-linked partially hydrolyzed polyvinyl acetate.

Suitable outer polymeric membranes include but are not limited to,polyethylene, polypropylene, ethylene/propylene copolymers,ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers,silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinatedpolyethylene, polyvinylchloride, vinyl chloride copolymers with vinylacetate, vinylidene chloride, ethylene and propylene, ionomerpolyethylene terephthalate, butyl rubber epichlorohydrin rubbers,ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcoholterpolymer, and ethylene/vinyloxyethanol copolymer.

C. Topical Administration

The pharmaceutical compositions provided herein can be administeredtopically to the skin, orifices, or mucosa. The topical administration,as used herein, includes (intra)dermal, conjunctival, intracorneal,intraocular, ophthalmic, auricular, transdermal, nasal, vaginal,urethral, respiratory, and rectal administration.

The pharmaceutical compositions provided herein can be formulated in anydosage forms that are suitable for topical administration for local orsystemic effect, including emulsions, solutions, suspensions, creams,gels, hydrogels, ointments, dusting powders, dressings, elixirs,lotions, suspensions, tinctures, pastes, foams, films, aerosols,irrigations, sprays, suppositories, bandages, and dermal patches. Thetopical formulation of the pharmaceutical compositions provided hereincan also comprise liposomes, micelles, microspheres, nanosystems, andmixtures thereof.

Pharmaceutically acceptable carriers and excipients suitable for use inthe topical formulations provided herein include, but are not limitedto, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles,antimicrobial agents or preservatives against the growth ofmicroorganisms, stabilizers, solubility enhancers, isotonic agents,buffering agents, antioxidants, local anesthetics, suspending anddispersing agents, wetting or emulsifying agents, complexing agents,sequestering or chelating agents, penetration enhancers,cryoprotectants, lyoprotectants, thickening agents, and inert gases.

The pharmaceutical compositions can also be administered topically byelectroporation, iontophoresis, phonophoresis, sonophoresis, ormicroneedle or needle-free injection, such as POWDERJECT™ (Chiron Corp.,Emeryville, Calif.), and BIOJECT™ (Bioject Medical Technologies Inc.,Tualatin, Oreg.).

The pharmaceutical compositions provided herein can be provided in theforms of ointments, creams, and gels. Suitable ointment vehicles includeoleaginous or hydrocarbon vehicles, including lard, benzoinated lard,olive oil, cottonseed oil, and other oils, white petrolatum;emulsifiable or absorption vehicles, such as hydrophilic petrolatum,hydroxystearin sulfate, and anhydrous lanolin; water-removable vehicles,such as hydrophilic ointment; water-soluble ointment vehicles, includingpolyethylene glycols of varying molecular weight; emulsion vehicles,either water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions,including cetyl alcohol, glyceryl monostearate, lanolin, and stearicacid (see, Remington: The Science and Practice of Pharmacy, supra).These vehicles are emollient but generally require addition ofantioxidants and preservatives.

Suitable cream base can be oil-in-water or water-in-oil. Suitable creamvehicles may be water-washable, and contain an oil phase, an emulsifier,and an aqueous phase. The oil phase is also called the “internal” phase,which is generally comprised of petrolatum and a fatty alcohol such ascetyl or stearyl alcohol. The aqueous phase usually, although notnecessarily, exceeds the oil phase in volume, and generally contains ahumectant. The emulsifier in a cream formulation may be a nonionic,anionic, cationic, or amphoteric surfactant.

Gels are semisolid, suspension-type systems. Single-phase gels containorganic macromolecules distributed substantially uniformly throughoutthe liquid carrier. Suitable gelling agents include, but are not limitedto, crosslinked acrylic acid polymers, such as carbomers,carboxypolyalkylenes, and CARBOPOL®; hydrophilic polymers, such aspolyethylene oxides, polyoxyethylene-polyoxypropylene copolymers, andpolyvinylalcohol; cellulosic polymers, such as hydroxypropyl cellulose,hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropylmethylcellulose phthalate, and methylcellulose; gums, such as tragacanthand xanthan gum; sodium alginate; and gelatin. In order to prepare auniform gel, dispersing agents such as alcohol or glycerin can be added,or the gelling agent can be dispersed by trituration, mechanical mixing,and/or stirring.

The pharmaceutical compositions provided herein can be administeredrectally, urethrally, vaginally, or perivaginally in the forms ofsuppositories, pessaries, bougies, poultices or cataplasm, pastes,powders, dressings, creams, plasters, contraceptives, ointments,solutions, emulsions, suspensions, tampons, gels, foams, sprays, orenemas. These dosage forms can be manufactured using conventionalprocesses as described in Remington: The Science and Practice ofPharmacy, supra.

Rectal, urethral, and vaginal suppositories are solid bodies forinsertion into body orifices, which are solid at ordinary temperaturesbut melt or soften at body temperature to release the activeingredient(s) inside the orifices. Pharmaceutically acceptable carriersutilized in rectal and vaginal suppositories include bases or vehicles,such as stiffening agents, which produce a melting point in theproximity of body temperature, when formulated with the pharmaceuticalcompositions provided herein; and antioxidants as described herein,including bisulfite and sodium metabisulfite. Suitable vehicles include,but are not limited to, cocoa butter (theobroma oil), glycerin-gelatin,carbowax (polyoxyethylene glycol), spermaceti, paraffin, white andyellow wax, and appropriate mixtures of mono-, di- and triglycerides offatty acids, and hydrogels, such as polyvinyl alcohol, hydroxyethylmethacrylate, and polyacrylic acid. Combinations of the various vehiclescan also be used. Rectal and vaginal suppositories may be prepared bycompressing or molding. The typical weight of a rectal and vaginalsuppository is about 2 to about 3 g.

The pharmaceutical compositions provided herein can be administeredophthalmically in the forms of solutions, suspensions, ointments,emulsions, gel-forming solutions, powders for solutions, gels, ocularinserts, and implants.

The pharmaceutical compositions provided herein can be administeredintranasally or by inhalation to the respiratory tract. Thepharmaceutical compositions can be provided in the form of an aerosol orsolution for delivery using a pressurized container, pump, spray,atomizer, such as an atomizer using electrohydrodynamics to produce afine mist, or nebulizer, alone or in combination with a suitablepropellant, such as 1,1,1,2-tetrafluoroethane or1,1,1,2,3,3,3-heptafluoropropane. The pharmaceutical compositions canalso be provided as a dry powder for insufflation, alone or incombination with an inert carrier such as lactose or phospholipids; andnasal drops. For intranasal use, the powder can comprise a bioadhesiveagent, including chitosan or cyclodextrin.

Solutions or suspensions for use in a pressurized container, pump,spray, atomizer, or nebulizer can be formulated to contain ethanol,aqueous ethanol, or a suitable alternative agent for dispersing,solubilizing, or extending release of the active ingredient providedherein; a propellant as solvent; and/or a surfactant, such as sorbitantrioleate, oleic acid, or an oligolactic acid.

The pharmaceutical compositions provided herein can be micronized to asize suitable for delivery by inhalation, such as about 50 micrometersor less, or about 10 micrometers or less. Particles of such sizes can beprepared using a comminuting method known to those skilled in the art,such as spiral jet milling, fluid bed jet milling, supercritical fluidprocessing to form nanoparticles, high pressure homogenization, or spraydrying.

Capsules, blisters, and cartridges for use in an inhaler or insufflatorcan be formulated to contain a powder mix of the pharmaceuticalcompositions provided herein; a suitable powder base, such as lactose orstarch; and a performance modifier, such as l-leucine, mannitol, ormagnesium stearate. The lactose may be anhydrous or in the form of themonohydrate. Other suitable excipients or carriers include, but are notlimited to, dextran, glucose, maltose, sorbitol, xylitol, fructose,sucrose, and trehalose. The pharmaceutical compositions provided hereinfor inhaled/intranasal administration can further comprise a suitableflavor, such as menthol and levomenthol; and/or sweeteners, such assaccharin and saccharin sodium.

The pharmaceutical compositions provided herein for topicaladministration can be formulated to be immediate release or modifiedrelease, including delayed-, sustained-, pulsed-, controlled-, targeted,and programmed release.

D. Modified Release

The pharmaceutical compositions provided herein can be formulated as amodified release dosage form. As used herein, the term “modifiedrelease” refers to a dosage form in which the rate or place of releaseof the active ingredient(s) is different from that of an immediatedosage form when administered by the same route. Modified release dosageforms include, but are not limited to, delayed-, extended-, prolonged-,sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-,programmed-release, and gastric retention dosage forms. Thepharmaceutical compositions in modified release dosage forms can beprepared using a variety of modified release devices and methods knownto those skilled in the art, including, but not limited to, matrixcontrolled release devices, osmotic controlled release devices,multiparticulate controlled release devices, ion-exchange resins,enteric coatings, multilayered coatings, microspheres, liposomes, andcombinations thereof. The release rate of the active ingredient(s) canalso be modified by varying the particle sizes and polymorphorism of theactive ingredient(s).

Examples of modified release include, but are not limited to, thosedescribed in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123;4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543;5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474;5,922,356; 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324;6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461;6,419,961; 6,589,548; 6,613,358; and 6,699,500.

1. Matrix Controlled Release Devices

The pharmaceutical compositions provided herein in a modified releasedosage form can be fabricated using a matrix controlled release deviceknown to those skilled in the art (see, Takada et al. in “Encyclopediaof Controlled Drug Delivery,” Vol. 2, Mathiowitz Ed., Wiley, 1999).

In certain embodiments, the pharmaceutical compositions provided hereinin a modified release dosage form is formulated using an erodible matrixdevice, which is water-swellable, erodible, or soluble polymers,including, but not limited to, synthetic polymers, and naturallyoccurring polymers and derivatives, such as polysaccharides andproteins.

Materials useful in forming an erodible matrix include, but are notlimited to, chitin, chitosan, dextran, and pullulan; gum agar, gumarabic, gum karaya, locust bean gum, gum tragacanth, carrageenans, gumghatti, guar gum, xanthan gum, and scleroglucan; starches, such asdextrin and maltodextrin; hydrophilic colloids, such as pectin;phosphatides, such as lecithin; alginates; propylene glycol alginate;gelatin; collagen; cellulosics, such as ethyl cellulose (EC),methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC,hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), celluloseacetate (CA), cellulose propionate (CP), cellulose butyrate (CB),cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetatetrimellitate (HPMCAT), and ethyl hydroxyethyl cellulose (EHEC);polyvinyl pyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerolfatty acid esters; polyacrylamide; polyacrylic acid; copolymers ofethacrylic acid or methacrylic acid (EUDRAGIT®, Rohm America, Inc.,Piscataway, N.J.); poly(2-hydroxyethyl-methacrylate); polylactides;copolymers of L-glutamic acid and ethyl-L-glutamate; degradable lacticacid-glycolic acid copolymers; poly-D-(−)-3-hydroxybutyric acid; andother acrylic acid derivatives, such as homopolymers and copolymers ofbutylmethacrylate, methyl methacrylate, ethyl methacrylate,ethylacrylate, (2-dimethylaminoethyl)methacrylate, and(trimethylaminoethyl)methacrylate chloride.

In certain embodiments, the pharmaceutical compositions provided hereinare formulated with a non-erodible matrix device. The activeingredient(s) is dissolved or dispersed in an inert matrix and isreleased primarily by diffusion through the inert matrix onceadministered. Materials suitable for use as a non-erodible matrix deviceinclude, but are not limited to, insoluble plastics, such aspolyethylene, polypropylene, polyisoprene, polyisobutylene,polybutadiene, polymethylmethacrylate, polybutylmethacrylate,chlorinated polyethylene, polyvinylchloride, methyl acrylate-methylmethacrylate copolymers, ethylene-vinyl acetate copolymers,ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, vinylchloride copolymers with vinyl acetate, vinylidene chloride, ethyleneand propylene, ionomer polyethylene terephthalate, butyl rubbers,epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer,ethylene/vinyloxyethanol copolymer, polyvinyl chloride, plasticizednylon, plasticized polyethylene terephthalate, natural rubber, siliconerubbers, polydimethylsiloxanes, and silicone carbonate copolymers;hydrophilic polymers, such as ethyl cellulose, cellulose acetate,crospovidone, and cross-linked partially hydrolyzed polyvinyl acetate;and fatty compounds, such as carnauba wax, microcrystalline wax, andtriglycerides.

In a matrix controlled release system, the desired release kinetics canbe controlled, for example, via the polymer type employed, the polymerviscosity, the particle sizes of the polymer and/or the activeingredient(s), the ratio of the active ingredient(s) versus the polymer,and other excipients or carriers in the compositions.

The pharmaceutical compositions provided herein in a modified releasedosage form can be prepared by methods known to those skilled in theart, including direct compression, dry or wet granulation followed bycompression, and melt-granulation followed by compression.

2. Osmotic Controlled Release Devices

The pharmaceutical compositions provided herein in a modified releasedosage form can be fabricated using an osmotic controlled releasedevice, including, but not limited to, one-chamber system, two-chambersystem, asymmetric membrane technology (AMT), and extruding core system(ECS). In general, such devices have at least two components: (a) a corewhich contains an active ingredient; and (b) a semipermeable membranewith at least one delivery port, which encapsulates the core. Thesemipermeable membrane controls the influx of water to the core from anaqueous environment of use so as to cause drug release by extrusionthrough the delivery port(s).

In addition to the active ingredient(s), the core of the osmotic deviceoptionally includes an osmotic agent, which creates a driving force fortransport of water from the environment of use into the core of thedevice. One class of osmotic agents is water-swellable hydrophilicpolymers, which are also referred to as “osmopolymers” and “hydrogels.”Suitable water-swellable hydrophilic polymers as osmotic agents include,but are not limited to, hydrophilic vinyl and acrylic polymers,polysaccharides such as calcium alginate, polyethylene oxide (PEO),polyethylene glycol (PEG), polypropylene glycol (PPG),poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic)acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol(PVA), PVA/PVP copolymers, PVA/PVP copolymers with hydrophobic monomerssuch as methyl methacrylate and vinyl acetate, hydrophilic polyurethanescontaining large PEO blocks, sodium croscarmellose, carrageenan,hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC),hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) andcarboxyethyl, cellulose (CEC), sodium alginate, polycarbophil, gelatin,xanthan gum, and sodium starch glycolate.

The other class of osmotic agents is osmogens, which are capable ofimbibing water to affect an osmotic pressure gradient across the barrierof the surrounding coating. Suitable osmogens include, but are notlimited to, inorganic salts, such as magnesium sulfate, magnesiumchloride, calcium chloride, sodium chloride, lithium chloride, potassiumsulfate, potassium phosphates, sodium carbonate, sodium sulfite, lithiumsulfate, potassium chloride, and sodium sulfate; sugars, such asdextrose, fructose, glucose, inositol, lactose, maltose, mannitol,raffinose, sorbitol, sucrose, trehalose, and xylitol; organic acids,such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleicacid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamicacid, p-toluenesulfonic acid, succinic acid, and tartaric acid; urea;and mixtures thereof.

Osmotic agents of different dissolution rates can be employed toinfluence how rapidly the active ingredient(s) is initially deliveredfrom the dosage form. For example, amorphous sugars, such as MANNOGEM™EZ (SPI Pharma, Lewes, Del.) can be used to provide faster deliveryduring the first couple of hours to promptly produce the desiredtherapeutic effect, and gradually and continually release of theremaining amount to maintain the desired level of therapeutic orprophylactic effect over an extended period of time. In this case, theactive ingredient(s) is released at such a rate to replace the amount ofthe active ingredient metabolized and excreted.

The core can also include a wide variety of other excipients andcarriers as described herein to enhance the performance of the dosageform or to promote stability or processing.

Materials useful in forming the semipermeable membrane include variousgrades of acrylics, vinyls, ethers, polyamides, polyesters, andcellulosic derivatives that are water-permeable and water-insoluble atphysiologically relevant pHs, or are susceptible to being renderedwater-insoluble by chemical alteration, such as crosslinking. Examplesof suitable polymers useful in forming the coating, include plasticized,unplasticized, and reinforced cellulose acetate (CA), cellulosediacetate, cellulose triacetate, CA propionate, cellulose nitrate,cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methylcarbamate, CA succinate, cellulose acetate trimellitate (CAT), CAdimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyloxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluenesulfonate, agar acetate, amylose triacetate, beta glucan acetate, betaglucan triacetate, acetaldehyde dimethyl acetate, triacetate of locustbean gum, hydroxylated ethylene-vinylacetate, EC, PEG, PPG, PEG/PPGcopolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT,poly(acrylic) acids and esters and poly-(methacrylic) acids and estersand copolymers thereof, starch, dextran, dextrin, chitosan, collagen,gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones,polystyrenes, polyvinyl halides, polyvinyl esters and ethers, naturalwaxes, and synthetic waxes.

Semipermeable membrane can also be a hydrophobic microporous membrane,wherein the pores are substantially filled with a gas and are not wettedby the aqueous medium but are permeable to water vapor, as disclosed inU.S. Pat. No. 5,798,119. Such hydrophobic but water-vapor permeablemembrane are typically composed of hydrophobic polymers such aspolyalkenes, polyethylene, polypropylene, polytetrafluoroethylene,polyacrylic acid derivatives, polyethers, polysulfones,polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidenefluoride, polyvinyl esters and ethers, natural waxes, and syntheticwaxes.

The delivery port(s) on the semipermeable membrane can be formedpost-coating by mechanical or laser drilling. Delivery port(s) can alsobe formed in situ by erosion of a plug of water-soluble material or byrupture of a thinner portion of the membrane over an indentation in thecore. In addition, delivery ports can be formed during coating process,as in the case of asymmetric membrane coatings of the type disclosed inU.S. Pat. Nos. 5,612,059 and 5,698,220.

The total amount of the active ingredient(s) released and the releaserate can substantially by modulated via the thickness and porosity ofthe semipermeable membrane, the composition of the core, and the number,size, and position of the delivery ports.

The pharmaceutical compositions in an osmotic controlled-release dosageform can further comprise additional conventional excipients or carriersas described herein to promote performance or processing of theformulation.

The osmotic controlled-release dosage forms can be prepared according toconventional methods and techniques known to those skilled in the art(see, Remington: The Science and Practice of Pharmacy, supra; Santus andBaker, J. Controlled Release 1995, 35, 1-21; Verma et al., DrugDevelopment and Industrial Pharmacy 2000, 26, 695-708; Verma et al., J.Controlled Release 2002, 79, 7-27).

In certain embodiments, the pharmaceutical compositions provided hereinare formulated as AMT controlled-release dosage form, which comprises anasymmetric osmotic membrane that coats a core comprising the activeingredient(s) and other pharmaceutically acceptable excipients orcarriers. See, U.S. Pat. No. 5,612,059 and WO 2002/17918. The AMTcontrolled-release dosage forms can be prepared according toconventional methods and techniques known to those skilled in the art,including direct compression, dry granulation, wet granulation, and adip-coating method.

In certain embodiments, the pharmaceutical compositions provided hereinare formulated as ESC controlled-release dosage form, which comprises anosmotic membrane that coats a core comprising the active ingredient(s),a hydroxylethyl cellulose, and other pharmaceutically acceptableexcipients or carriers.

3. Multiparticulate Controlled Release Devices

The pharmaceutical compositions provided herein in a modified releasedosage form can be fabricated as a multiparticulate controlled releasedevice, which comprises a multiplicity of particles, granules, orpellets, ranging from about 10 μm to about 3 mm, about 50 μm to about2.5 mm, or from about 100 μm to about 1 mm in diameter. Suchmultiparticulates can be made by the processes known to those skilled inthe art, including wet- and dry-granulation, extrusion/spheronization,roller-compaction, melt-congealing, and by spray-coating seed cores.See, for example, Multiparticulate Oral Drug Delivery; Marcel Dekker:1994; and Pharmaceutical Pelletization Technology; Marcel Dekker: 1989.

Other excipients or carriers as described herein can be blended with thepharmaceutical compositions to aid in processing and forming themultiparticulates. The resulting particles can themselves constitute themultiparticulate device or can be coated by various film-formingmaterials, such as enteric polymers, water-swellable, and water-solublepolymers. The multiparticulates can be further processed as a capsule ora tablet.

4. Targeted Delivery

The pharmaceutical compositions provided herein can also be formulatedto be targeted to a particular tissue, receptor, or other area of thebody of the subject to be treated, including liposome-, resealederythrocyte-, and antibody-based delivery systems. Examples include, butare not limited to, those disclosed in U.S. Pat. Nos. 6,316,652;6,274,552; 6,271,359; 6,253,872; 6,139,865; 6,131,570; 6,120,751;6,071,495; 6,060,082; 6,048,736; 6,039,975; 6,004,534; 5,985,307;5,972,366; 5,900,252; 5,840,674; 5,759,542; and 5,709,874.

Methods of Use

In one embodiment, provided is a method of treating, preventing, orameliorating one or more symptoms of a disorder, disease, or conditionassociated with PI3K activity in a subject, which comprisesadministering to the subject a therapeutically effective amount of acompound provided herein, e.g., a compound of Formula IA, IB, or IC,including an enantiomer, a mixture of enantiomers, or a mixture of twoor more diastereomers thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.

In another embodiments, provided is a method of treating, preventing, orameliorating one or more symptoms of a disorder, disease, or conditionresponsive to the modulation of PI3K activity in a subject, whichcomprises administering to the subject a therapeutically effectiveamount of a compound provided herein, e.g., a compound of Formula IA,IB, or IC, including an enantiomer, a mixture of enantiomers, or amixture of two or more diastereomers thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.

In yet another embodiment, provided is a method of treating, preventing,or ameliorating one or more symptoms of a disorder, disease, orcondition mediated by a PI3K enzyme in a subject, which comprisesadministering to the subject a therapeutically effective amount of acompound provided herein, e.g., a compound of Formula IA, IB, or IC,including an enantiomer, a mixture of enantiomers, or a mixture of twoor more diastereomers thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.

In yet another embodiment, provided is a method of treating, preventing,or ameliorating one or more symptoms of cancer in a subject, whichcomprises administering to the subject a therapeutically effectiveamount of a compound provided herein, e.g., a compound of Formula IA,IB, or IC, including an enantiomer, a mixture of enantiomers, or amixture of two or more diastereomers thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.

In yet another embodiment, provided herein are uses of a compoundprovided herein, e.g., a compound of Formula IA, IB, or IC, including anenantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof; or a pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof, in the manufacture of a medicament for thetreatment of cancer.

In certain embodiments, the compound selectively targets the p110αsubunit of PI3K. In certain embodiments, the compound selectivelyinhibits the PI3K via its interaction with its p110α subunit. In certainembodiments, the compound selectively alkylates the p110α subunit ofPI3K.

In certain embodiments, the PI3K is a wild type PI3K. In certainembodiments, the PI3K is a PI3K mutant.

In certain embodiments, the PI3K is a Class I kinase. In certainembodiments, the PI3K is p110α, p110β, p110δ, or p110γ. In certainembodiments, the PI3K is a wild type of a Class I kinase. In certainembodiments, the PI3K is a mutant of a Class I kinase.

In certain embodiments, the PI3K is p110α. In certain embodiments, thePI3K is a wild type of p110α. In certain embodiments, the PI3K is ap110α mutant. In certain embodiments, the p110α mutant is R38H, G106V,K111N, K227E, N345K, C420R, P539R, E542K, E545A, E545G, E545K, Q546K,Q546P, E453Q, H710P, I800L, T1025S, M1043I, M1043V, H1047L, H1047R, orH1047Y. In certain embodiments, the p110α mutant is R38H, K111N, N345K,C420R, P539R, E542K, E545A, E545G, E545K, Q546K, Q546P, I800L, T1025S,M1043I, H1047L, H1047R, or H1047Y. In certain embodiments, the p110αmutant is C420R, E542K, E545A, E545K, Q546K, I800L, M1043I, H1047L, orH1047Y.

In certain embodiments, the PI3K is a Class IV kinase. In certainembodiments, the PI3K is a wild type of a Class IV kinase. In certainembodiments, the PI3K is a mutant of a Class IV kinase. In certainembodiments, the PI3K is mTOR, ATM, ATR, or DNA-PK. In certainembodiments, the PI3K is mTOR.

In one embodiment, the subject is a mammal. In another embodiment, thesubject is a human. In yet another embodiment, the subject is a primateother than a human, a farm animal such as cattle, a sport animal, or apet such as a horse, dog, or cat.

The disorders, diseases, or conditions treatable with a compoundprovided herein, include, but are not limited to, (1) inflammatory orallergic diseases, including systemic anaphylaxis and hypersensitivitydisorders, atopic dermatitis, urticaria, drug allergies, insect stingallergies, food allergies (including celiac disease and the like), andmastocytosis; (2) inflammatory bowel diseases, including Crohn'sdisease, ulcerative colitis, ileitis, and enteritis; (3) vasculitis, andBehcet's syndrome; (4) psoriasis and inflammatory dermatoses, includingdermatitis, eczema, atopic dermatitis, allergic contact dermatitis,urticaria, viral cutaneous pathologies including those derived fromhuman papillomavirus, HIV or RLV infection, bacterial, flugal, and otherparasital cutaneous pathologies, and cutaneous lupus erythematosus; (5)asthma and respiratory allergic diseases, including allergic asthma,exercise induced asthma, allergic rhinitis, otitis media, allergicconjunctivitis, hypersensitivity lung diseases, and chronic obstructivepulmonary disease; (6) autoimmune diseases, including arthritis(including rheumatoid and psoriatic), systemic lupus erythematosus, typeI diabetes, myasthenia gravis, multiple sclerosis, Graves' disease, andglomerulonephritis; (7) graft rejection (including allograft rejectionand graft-v-host disease), e.g., skin graft rejection, solid organtransplant rejection, bone marrow transplant rejection; (8) fever; (9)cardiovascular disorders, including acute heart failure, hypotension,hypertension, angina pectoris, myocardial infarction, cardiomyopathy,congestive heart failure, atherosclerosis, coronary artery disease,restenosis, and vascular stenosis; (10) cerebrovascular disorders,including traumatic brain injury, stroke, ischemic reperfusion injuryand aneurysm; (11) cancers of the breast, skin, prostate, cervix,uterus, ovary, testes, bladder, lung, liver, larynx, oral cavity, colonand gastrointestinal tract (e.g., esophagus, stomach, pancreas), brain,thyroid, blood, and lymphatic system; (12) fibrosis, connective tissuedisease, and sarcoidosis, (13) genital and reproductive conditions,including erectile dysfunction; (14) gastrointestinal disorders,including gastritis, ulcers, nausea, pancreatitis, and vomiting; (15)neurologic disorders, including Alzheimer's disease; (16) sleepdisorders, including insomnia, narcolepsy, sleep apnea syndrome, andPickwick Syndrome; (17) pain; (18) renal disorders; (19) oculardisorders, including glaucoma; and (20) infectious diseases, includingHIV.

In certain embodiments, the cancer treatable with the methods providedherein includes, but is not limited to, (1) leukemias, including, butnot limited to, acute leukemia, acute lymphocytic leukemia, acutemyelocytic leukemias such as myeloblastic, promyelocytic,myelomonocytic, monocytic, erythroleukemia leukemias and myelodysplasticsyndrome or a symptom thereof (such as anemia, thrombocytopenia,neutropenia, bicytopenia or pancytopenia), refractory anemia (RA), RAwith ringed sideroblasts (RARS), RA with excess blasts (RAEB), RAEB intransformation (RAEB-T), preleukemia, and chronic myelomonocyticleukemia (CMML), (2) chronic leukemias, including, but not limited to,chronic myelocytic (granulocytic) leukemia, chronic lymphocyticleukemia, and hairy cell leukemia; (3) polycythemia vera; (4) lymphomas,including, but not limited to, Hodgkin's disease and non-Hodgkin'sdisease; (5) multiple myelomas, including, but not limited to,smoldering multiple myeloma, nonsecretory myeloma, osteoscleroticmyeloma, plasma cell leukemia, solitary plasmacytoma, and extramedullaryplasmacytoma; (6) Waldenström's macroglobulinemia; (7) monoclonalgammopathy of undetermined significance; (8) benign monoclonalgammopathy; (9) heavy chain disease; (10) bone and connective tissuesarcomas, including, but not limited to, bone sarcoma, osteosarcoma,chondrosarcoma, Ewing's sarcoma, malignant giant cell tumor,fibrosarcoma of bone, chordoma, periosteal sarcoma, soft-tissuesarcomas, angiosarcoma (hemangiosarcoma), fibrosarcoma, Kaposi'ssarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, metastaticcancers, neurilemmoma, rhabdomyosarcoma, and synovial sarcoma; (11)brain tumors, including, but not limited to, glioma, astrocytoma, brainstem glioma, ependymoma, oligodendroglioma, nonglial tumor, acousticneurinoma, craniopharyngioma, medulloblastoma, meningioma, pineocytoma,pineoblastoma, and primary brain lymphoma; (12) breast cancer,including, but not limited to, adenocarcinoma, lobular (small cell)carcinoma, intraductal carcinoma, medullary breast cancer, mucinousbreast cancer, tubular breast cancer, papillary breast cancer, primarycancers, Paget's disease, and inflammatory breast cancer; (13) adrenalcancer, including, but not limited to, pheochromocytom andadrenocortical carcinoma; (14) thyroid cancer, including, but notlimited to, papillary or follicular thyroid cancer, medullary thyroidcancer, and anaplastic thyroid cancer; (15) pancreatic cancer,including, but not limited to, insulinoma, gastrinoma, glucagonoma,vipoma, somatostatin-secreting tumor, and carcinoid or islet cell tumor;(16) pituitary cancer, including, but limited to, Cushing's disease,prolactin-secreting tumor, acromegaly, and diabetes insipius; (17) eyecancer, including, but not limited, to ocular melanoma such as irismelanoma, choroidal melanoma, and cilliary body melanoma, andretinoblastoma; (18) vaginal cancer, including, but not limited to,squamous cell carcinoma, adenocarcinoma, and melanoma; (19) vulvarcancer, including, but not limited to, squamous cell carcinoma,melanoma, adenocarcinoma, basal cell carcinoma, sarcoma, and Paget'sdisease; (20) cervical cancers, including, but not limited to, squamouscell carcinoma, and adenocarcinoma; (21) uterine cancer, including, butnot limited to, endometrial carcinoma and uterine sarcoma; (22) ovariancancer, including, but not limited to, ovarian epithelial carcinoma,borderline tumor, germ cell tumor, and stromal tumor; (23) esophagealcancer, including, but not limited to, squamous cancer, adenocarcinoma,adenoid cystic carcinoma, mucoepidermoid carcinoma, adenosquamouscarcinoma, sarcoma, melanoma, plasmacytoma, verrucous carcinoma, and oatcell (small cell) carcinoma; (24) stomach cancer, including, but notlimited to, adenocarcinoma, fungating (polypoid), ulcerating,superficial spreading, diffusely spreading, malignant lymphoma,liposarcoma, fibrosarcoma, and carcinosarcoma; (25) colon cancer; (26)rectal cancer; (27) liver cancer, including, but not limited to,hepatocellular carcinoma and hepatoblastoma; (28) gallbladder cancer,including, but not limited to, adenocarcinoma; (29) cholangiocarcinomas,including, but not limited to, pappillary, nodular, and diffuse; (30)lung cancer, including, but not limited to, non-small cell lung cancer,squamous cell carcinoma (epidermoid carcinoma), adenocarcinoma,large-cell carcinoma, and small-cell lung cancer; (31) testicularcancer, including, but not limited to, germinal tumor, seminoma,anaplastic, classic (typical), spermatocytic, nonseminoma, embryonalcarcinoma, teratoma carcinoma, and choriocarcinoma (yolk-sac tumor);(32) prostate cancer, including, but not limited to, adenocarcinoma,leiomyosarcoma, and rhabdomyosarcoma; (33) penal cancer; (34) oralcancer, including, but not limited to, squamous cell carcinoma; (35)basal cancer; (36) salivary gland cancer, including, but not limited to,adenocarcinoma, mucoepidermoid carcinoma, and adenoidcystic carcinoma;(37) pharynx cancer, including, but not limited to, squamous cell cancerand verrucous; (38) skin cancer, including, but not limited to, basalcell carcinoma, squamous cell carcinoma and melanoma, superficialspreading melanoma, nodular melanoma, lentigo malignant melanoma, andacral lentiginous melanoma; (39) kidney cancer, including, but notlimited to, renal cell cancer, adenocarcinoma, hypernephroma,fibrosarcoma, and transitional cell cancer (renal pelvis and/or uterer);(40) Wilms' tumor; (41) bladder cancer, including, but not limited to,transitional cell carcinoma, squamous cell cancer, adenocarcinoma, andcarcinosarcoma; and other cancer, including, not limited to,myxosarcoma, osteogenic sarcoma, endotheliosarcoma,lymphangio-endotheliosarcoma, mesothelioma, synovioma, hemangioblastoma,epithelial carcinoma, cystadenocarcinoma, bronchogenic carcinoma, sweatgland carcinoma, sebaceous gland carcinoma, papillary carcinoma, andpapillary adenocarcinomas (See Fishman et al., 1985, Medicine, 2d Ed.,J.B. Lippincott Co., Philadelphia and Murphy et al., 1997, InformedDecisions: The Complete Book of Cancer Diagnosis, Treatment, andRecovery, Viking Penguin, Penguin Books U.S.A., Inc., United States ofAmerica).

Depending on the disorder, disease, or condition to be treated, and thesubject's condition, the compounds or pharmaceutical compositionsprovided herein can be administered by oral, parenteral (e.g.,intramuscular, intraperitoneal, intravenous, ICV, intracistemalinjection or infusion, subcutaneous injection, or implant), inhalation,nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal orlocal) routes of administration and can be formulated, alone ortogether, in suitable dosage unit with pharmaceutically acceptableexcipients, carriers, adjuvants, and vehicles appropriate for each routeof administration. Also provided is administration of the compounds orpharmaceutical compositions provided herein in a depot formulation, inwhich the active ingredient is released over a predefined time period.

In the treatment, prevention, or amelioration of one or more symptoms ofthe disorders, diseases, or conditions described herein, an appropriatedosage level generally is ranging from about 0.001 to 100 mg per kgsubject body weight per day (mg/kg per day), from about 0.01 to about 75mg/kg per day, from about 0.1 to about 50 mg/kg per day, from about 0.5to about 25 mg/kg per day, or from about 1 to about 20 mg/kg per day,which can be administered in single or multiple doses. Within thisrange, the dosage can be ranging from about 0.005 to about 0.05, fromabout 0.05 to about 0.5, from about 0.5 to about 5.0, from about 1 toabout 15, from about 1 to about 20, or from about 1 to about 50 mg/kgper day.

For oral administration, the pharmaceutical compositions provided hereincan be formulated in the form of tablets containing from about 1.0 toabout 1,000 mg of the active ingredient, in one embodiment, about 1,about 5, about 10, about 15, about 20, about 25, about 50, about 75,about 100, about 150, about 200, about 250, about 300, about 400, about500, about 600, about 750, about 800, about 900, and about 1,000 mg ofthe active ingredient for the symptomatic adjustment of the dosage tothe patient to be treated. The pharmaceutical compositions can beadministered on a regimen of 1 to 4 times per day, including once,twice, three times, and four times per day.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient can be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

Also provided herein are methods of modulating PI3K activity, comprisingcontacting a PIK3 enzyme with a compound provided herein, e.g., acompound of Formula IA, IB, or IC, including an enantiomer, a mixture ofenantiomers, or a mixture of two or more diastereomers thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.In one embodiment, the PIK3 enzyme is inside a cell.

In certain embodiments, the PI3K is a wild type PI3K. In certainembodiments, the PI3K is a PI3K mutant.

In certain embodiments, the PI3K is a Class I kinase. In certainembodiments, the PI3K is p110α, p110β, p110δ, or p110γ. In certainembodiments, the PI3K is a wild type of a Class I kinase. In certainembodiments, the PI3K is a mutant of a Class I kinase.

In certain embodiments, the PI3K is p110α. In certain embodiments, thePI3K is a wild type of p110α. In certain embodiments, the PI3K is ap110α mutant. In certain embodiments, the p110α mutant is R38H, G106V,K111N, K227E, N345K, C420R, P539R, E542K, E545A, E545G, E545K, Q546K,Q546P, E453Q, H710P, 1800L, T1025S, M1043I, M1043V, H1047L, H1047R, orH1047Y. In certain embodiments, the p110α mutant is R38H, K111N, N345K,C420R, P539R, E542K, E545A, E545G, E545K, Q546K, Q546P, 1800L, T1025S,M1043I, H1047L, H1047R, or H1047Y. In certain embodiments, the p110αmutant is C420R, E542K, E545A, E545K, Q546K, I800L, M1043I, H1047L, orH1047Y.

In certain embodiments, the PI3K is a Class IV kinase. In certainembodiments, the PI3K is a wild type of a Class IV kinase. In certainembodiments, the PI3K is a mutant of a Class IV kinase. In certainembodiments, the PI3K is mTOR, ATM, ATR, or DNA-PK. In certainembodiments, the PI3K is mTOR.

In certain embodiments, the compounds provided herein, e.g., a compoundof Formula IA, IB, or IC, including an enantiomer, a mixture ofenantiomers, or a mixture of two or more diastereomers thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof,show inhibitory activity against a PI3K and a mutant thereof.

In certain embodiments, the compounds provided herein, e.g., a compoundof Formula IA, IB, or IC, including an enantiomer, a mixture ofenantiomers, or a mixture of two or more diastereomers thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof,show inhibitory activity against a wild type of a PI3K. In certainembodiments, the PI3K is p110α. In certain embodiments, the PI3K ismTOR.

In certain embodiments, the compounds provided herein, e.g., a compoundof Formula IA, IB, or IC, including an enantiomer, a mixture ofenantiomers, or a mixture of two or more diastereomers thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof,show inhibitory activity against a PI3K mutant. In certain embodiments,the PI3K mutant is a p110α mutant. In certain embodiments, the p110αmutant is C420R, E542K, E545A, E545K, Q546K, I800L, M1043I, H1047L, orH1047Y.

The compounds provided herein, e.g., a compound of Formula IA, IB, orIC, including an enantiomer, a mixture of enantiomers, or a mixture oftwo or more diastereomers thereof; or a pharmaceutically acceptablesalt, solvate, hydrate, or prodrug thereof, can also be combined or usedin combination with other agents or therapies useful in the treatment,prevention, or amelioration of one or more symptoms of the disorders,diseases, or conditions for which the compounds provided herein areuseful, including asthma, allergic rhinitis, eczema, psoriasis, atopicdermatitis, fever, sepsis, systemic lupus erythematosus, diabetes,rheumatoid arthritis, multiple sclerosis, atherosclerosis, transplantrejection, inflammatory bowel disease, cancer, infectious diseases, andthose pathologies noted herein.

Suitable other therapeutic agents can also include, but are not limitedto, (1) alpha-adrenergic agents; (2) antiarrhythmic agents; (3)anti-atherosclerotic agents, such as ACAT inhibitors; (4) antibiotics,such as anthracyclines, bleomycins, mitomycin, dactinomycin, andplicamycin; (5) anticancer agents and cytotoxic agents, e.g., alkylatingagents, such as nitrogen mustards, alkyl sulfonates, nitrosoureas,ethylenimines, and triazenes; (6) anticoagulants, such as acenocoumarol,argatroban, bivalirudin, lepirudin, fondaparinux, heparin, phenindione,warfarin, and ximelagatran; (7) anti-diabetic agents, such as biguanides(e.g., metformin), glucosidase inhibitors (e.g., acarbose), insulins,meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride,glyburide, and glipizide), thiozolidinediones (e.g., troglitazone,rosiglitazone, and pioglitazone), and PPAR-gamma agonists; (8)antifungal agents, such as amorolfine, amphotericin B, anidulafungin,bifonazole, butenafine, butoconazole, caspofungin, ciclopirox,clotrimazole, econazole, fenticonazole, filipin, fluconazole,isoconazole, itraconazole, ketoconazole, micafungin, miconazole,naftifine, natamycin, nystatin, oxyconazole, ravuconazole, posaconazole,rimocidin, sertaconazole, sulconazole, terbinafine, terconazole,tioconazole, and voriconazole; (9) antiinflammatories, e.g.,non-steroidal anti-inflammatory agents, such as aceclofenac, acemetacin,amoxiprin, aspirin, azapropazone, benorilate, bromfenac, carprofen,celecoxib, choline magnesium salicylate, diclofenac, diflunisal,etodolac, etoricoxib, faislamine, fenbufen, fenoprofen, flurbiprofen,ibuprofen, indometacin, ketoprofen, ketorolac, lornoxicam, loxoprofen,lumiracoxib, meclofenamic acid, mefenamic acid, meloxicam, metamizole,methyl salicylate, magnesium salicylate, nabumetone, naproxen,nimesulide, oxyphenbutazone, parecoxib, phenylbutazone, piroxicam,salicyl salicylate, sulindac, sulfinpyrazone, suprofen, tenoxicam,tiaprofenic acid, and tolmetin; (10) antimetabolites, such as folateantagonists, purine analogues, and pyrimidine analogues; (11)anti-platelet agents, such as GPIIb/IIIa blockers (e.g., abciximab,eptifibatide, and tirofiban), P2Y(AC) antagonists (e.g., clopidogrel,ticlopidine and CS-747), cilostazol, dipyridamole, and aspirin; (12)antiproliferatives, such as methotrexate, FK506 (tacrolimus), andmycophenolate mofetil; (13) anti-TNF antibodies or soluble TNF receptor,such as etanercept, rapamycin, and leflunimide; (14) aP2 inhibitors;(15) beta-adrenergic agents, such as carvedilol and metoprolol; (16)bile acid sequestrants, such as questran; (17) calcium channel blockers,such as amlodipine besylate; (18) chemotherapeutic agents; (19)cyclooxygenase-2 (COX-2) inhibitors, such as celecoxib and rofecoxib;(20) cyclosporins; (21) cytotoxic drugs, such as azathioprine andcyclophosphamide; (22) diuretics, such as chlorothiazide,hydrochlorothiazide, flumethiazide, hydroflumethiazide,bendroflumethiazide, methylchlorothiazide, trichloromethiazide,polythiazide, benzothiazide, ethacrynic acid, ticrynafen,chlorthalidone, furosenide, muzolimine, bumetanide, triamterene,amiloride, and spironolactone; (23) endothelin converting enzyme (ECE)inhibitors, such as phosphoramidon; (24) enzymes, such asL-asparaginase; (25) Factor VIIa Inhibitors and Factor Xa Inhibitors;(26) farnesyl-protein transferase inhibitors; (27) fibrates; (28) growthfactor inhibitors, such as modulators of PDGF activity; (29) growthhormone secretagogues; (30) HMG CoA reductase inhibitors, such aspravastatin, lovastatin, atorvastatin, simvastatin, NK-104 (a.k.a.itavastatin, nisvastatin, or nisbastatin), and ZD-4522 (also known asrosuvastatin, atavastatin, or visastatin); neutral endopeptidase (NEP)inhibitors; (31) hormonal agents, such as glucocorticoids (e.g.,cortisone), estrogens/antiestrogens, androgens/antiandrogens,progestins, and luteinizing hormone-releasing hormone antagonists, andoctreotide acetate; (32) immunosuppressants; (33) mineralocorticoidreceptor antagonists, such as spironolactone and eplerenone; (34)microtubule-disruptor agents, such as ecteinascidins; (35)microtubule-stabilizing agents, such as pacitaxel, docetaxel, andepothilones A-F; (36) MTP Inhibitors; (37) niacin; (38)phosphodiesterase inhibitors, such as PDE III inhibitors (e.g.,cilostazol) and PDE V inhibitors (e.g., sildenafil, tadalafil, andvardenafil); (39) plant-derived products, such as vinca alkaloids,epipodophyllotoxins, and taxanes; (40) platelet activating factor (PAF)antagonists; (41) platinum coordination complexes, such as cisplatin,satraplatin, and carboplatin; (42) potassium channel openers; (43)prenyl-protein transferase inhibitors; (44) protein tyrosine kinaseinhibitors; (45) renin inhibitors; (46) squalene synthetase inhibitors;(47) steroids, such as aldosterone, beclometasone, betamethasone,deoxycorticosterone acetate, fludrocortisone, hydrocortisone (cortisol),prednisolone, prednisone, methylprednisolone, dexamethasone, andtriamcinolone; (48) TNF-alpha inhibitors, such as tenidap; (49) thrombininhibitors, such as hirudin; (50) thrombolytic agents, such asanistreplase, reteplase, tenecteplase, tissue plasminogen activator(tPA), recombinant tPA, streptokinase, urokinase, prourokinase, andanisoylated plasminogen streptokinase activator complex (APSAC); (51)thromboxane receptor antagonists, such as ifetroban; (52) topoisomeraseinhibitors; (53) vasopeptidase inhibitors (dual NEP-ACE inhibitors),such as omapatrilat and gemopatrilat; and (54) other miscellaneousagents, such as, hydroxyurea, procarbazine, mitotane,hexamethylmelamine, and gold compounds.

In certain embodiments, the other therapies that may be used incombination with the compounds provided herein include, but are notlimited to, surgery, endocrine therapy, biologic response modifiers(e.g., interferons, interleukins, and tumor necrosis factor (TNF)),hyperthermia and cryotherapy, and agents to attenuate any adverseeffects (e.g., antiemetics).

In certain embodiments, the other therapeutic agents that may be used incombination with the compounds provided herein include, but are notlimited to, alkylating drugs (mechlorethamine, chlorambucil,cyclophosphamide, melphalan, and ifosfamide), antimetabolites(cytarabine (also known as cytosine arabinoside or Ara-C), HDAC (highdose cytarabine), and methotrexate), purine antagonists and pyrimidineantagonists (6-mercaptopurine, 5-fluorouracil, cytarbine, andgemcitabine), spindle poisons (vinblastine, vincristine, andvinorelbine), podophyllotoxins (etoposide, irinotecan, and topotecan),antibiotics (daunorubicin, doxorubicin, bleomycin, and mitomycin),nitrosoureas (carmustine and lomustine), enzymes (asparaginase), andhormones (tamoxifen, leuprolide, flutamide, and megestrol), imatinib,adriamycin, dexamethasone, and cyclophosphamide. For a morecomprehensive discussion of updated cancer therapies; See,http://www.nci.nih.gov/, a list of the FDA approved oncology drugs athttp://www.fda.gov/cder/cancer/druglistframe.htm, and The Merck Manual,Seventeenth Ed. 1999, the entire contents of which are herebyincorporated by reference.

In another embodiment, the method provided herein comprisesadministration of a compound of Formula IA, IB, or IC, together withadministering one or more chemotherapeutic agents and/or therapiesselected from: alkylation agents (e.g., cisplatin, carboplatin);antimetabolites (e.g., methotrexate and 5-FU); antitumour antibiotics(e.g., adriamymycin and bleomycin); antitumour vegetable alkaloids(e.g., taxol and etoposide); antitumor hormones (e.g., dexamethasone andtamoxifen); antitumour immunological agents (e.g., interferon α, β, andγ); radiation therapy; and surgery. In certain embodiments, the one ormore chemotherapeutic agents and/or therapies are administered to thesubject before, during, or after the administration of the compound ofFormula IA, IB, or IC as defined herein.

Such other agents, or drugs, can be administered, by a route and in anamount commonly used therefor, simultaneously or sequentially with thecompounds provided herein, e.g., a compound of Formula IA, IB, or IC,including a single enantiomer, a mixture of enantiomers, or a mixture ofdiastereomers thereof; or a pharmaceutically acceptable salt, solvate,or prodrug thereof. When a compound provided herein is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compoundprovided herein can be utilized, but is not required. Accordingly, thepharmaceutical compositions provided herein include those that alsocontain one or more other active ingredients or therapeutic agents, inaddition to a compound provided herein.

The weight ratio of a compound provided herein to the second activeingredient can be varied, and will depend upon the effective dose ofeach ingredient. Generally, an effective dose of each will be used.Thus, for example, when a compound provided herein is combined with aNSAID, the weight ratio of the compound to the NSAID can range fromabout 1,000:1 to about 1:1,000, or about 200:1 to about 1:200.Combinations of a compound provided herein and other active ingredientswill generally also be within the aforementioned range, but in eachcase, an effective dose of each active ingredient should be used.

The compounds provided herein can also be provided as an article ofmanufacture using packaging materials well known to those of skill inthe art. See, e.g., U.S. Pat. Nos. 5,323,907; 5,052,558; and 5,033,252.Examples of pharmaceutical packaging materials include, but are notlimited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials,containers, syringes, and any packaging material suitable for a selectedformulation and intended mode of administration and treatment.

Provided herein also are kits which, when used by the medicalpractitioner, can simplify the administration of appropriate amounts ofactive ingredients to a subject. In certain embodiments, the kitprovided herein includes a container and a dosage form of a compoundprovided herein, including a single enantiomer or a mixture ofdiastereomers thereof; or a pharmaceutically acceptable salt, solvate,or prodrug thereof.

In certain embodiments, the kit includes a container comprising a dosageform of the compound provided herein, including a single enantiomer or amixture of diastereomers thereof; or a pharmaceutically acceptable salt,solvate, or prodrug thereof, in a container comprising one or more othertherapeutic agent(s) described herein.

Kits provided herein can further include devices that are used toadminister the active ingredients. Examples of such devices include, butare not limited to, syringes, needle-less injectors drip bags, patches,and inhalers. The kits provided herein can also include condoms foradministration of the active ingredients.

Kits provided herein can further include pharmaceutically acceptablevehicles that can be used to administer one or more active ingredients.For example, if an active ingredient is provided in a solid form thatmust be reconstituted for parenteral administration, the kit cancomprise a sealed container of a suitable vehicle in which the activeingredient can be dissolved to form a particulate-free sterile solutionthat is suitable for parenteral administration. Examples ofpharmaceutically acceptable vehicles include, but are not limited to:aqueous vehicles, including, but not limited to, Water for InjectionUSP, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection,Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection;water-miscible vehicles, including, but not limited to, ethyl alcohol,polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles,including, but not limited to, corn oil, cottonseed oil, peanut oil,sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

The disclosure will be further understood by the following non-limitingexamples.

EXAMPLES

As used herein, the symbols and conventions used in these processes,schemes and examples, regardless of whether a particular abbreviation isspecifically defined, are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry. Specifically, butwithout limitation, the following abbreviations may be used in theexamples and throughout the specification: g (grams); mg (milligrams);mL (milliliters); μL (microliters); M (molar); mM (millimolar); μM(micromolar); eq. (equivalent); mmol (millimoles); Hz (Hertz); MHz(megahertz); hr or hrs (hours); min (minutes); MS (mass spectrometry);APCI (atmospheric pressure chemical ionization); mp (melting point); DMF(dimethyformamide); DMSO (dimethylsulfoxide); DMSO-d₆ (deuterateddimethylsulfoxide); EtOAc (ethyl acetate); EtOH (ethanol); MeOH(methanol); THF (tetrahydrofuran); DIPEA (N,N-diisopropylethylamine);TFA (trifluoroacetic acid); Me (methyl); Et (ethyl); PdCl₂(dppf),((1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II)); and EDTA(ethylenediaminetetraacetic acid).

For all of the following examples, standard work-up and purificationmethods known to those skilled in the art can be utilized. Unlessotherwise indicated, all temperatures are expressed in ° C. (degreesCentigrade). All reactions conducted at room temperature unlessotherwise noted. Synthetic methodologies illustrated herein are intendedto exemplify the applicable chemistry through the use of specificexamples and are not indicative of the scope of the disclosure.

General Experimental Information.

Elemental analyses (combustion analysis) were carried out in theMicrochemical Laboratory, University of Otago, Dunedin, NZ. Meltingpoints were determined on an Electrothermal 9100 Melting PointApparatus. NMR spectra were obtained on a Bruker Avance-400 spectrometerat 400 MHz for ¹H and 100 MHz for ¹³C spectra, referenced to TMS(Si(CH₃)₄). Mass spectra were determined on a VG-70SE mass spectrometerusing an ionizing potential of 70 eV at a nominal resolution of 1000.High-resolution spectra were obtained at nominal resolutions of 3000,5000, or 10000 as appropriate. All MS spectra were obtained as electronimpact (EI) using perfluorokerosene (PFK) as a reference unlessotherwise stated. Column chromatography was carried out on silica gel(Merck 230-400 mesh), unless otherwise stated.

Example 1 Synthesis of2-(difluoromethyl)-1-[4-[4-(methylsulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole

A solution of 100 mg (0.24 mmol) of2-(difluoromethyl)-1-[4-(4-morpholinyl)-6-(1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole(WO 2006/095906) and 0.51 g (50 mmol) of Et₃N in 20 mL of THF was cooledto 0° C. and 41 mg (0.36 mmol) of methanesulfonyl chloride was added.The mixture was allowed to warm to room temperature, and after 1 hrwater was added. The precipitate was collected, washed with water, anddried to give 110 mg (93% yield) of2-(difluoromethyl)-1-[4-[4-(methylsulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole:mp (MeOH) 248-250° C.; ¹H NMR (CDCl₃) δ 8.30 (br d, J=8.3 Hz, 1H), 7.90(br d, J=7.3 Hz, 1H), 7.52 (t, J_(HF)=53.6 Hz, 1H), 7.46-7.40 (m, 2H),4.03 (m, 4H), 3.89 (m, 4H), 3.80 (m, 4H), 3.34 (m, 4H), 2.82 (s, 3H);Anal. Calcd. for C₂₀H₂₄F₂N₈O₄S: C, 48.6; H, 4.9; N, 22.7. Found: C,48.8; H, 4.9; N, 22.85%.

Example 2 Synthesis of2-(difluoromethyl)-4-methoxy-1-[4-[4-(methylsulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole

2-Amino-3-methoxynitrobenzene (15.10 g, 0.09 mol) was hydrogenated overpalladium on carbon in methanol, and the solution was filtered throughcelite into a methanolic HCl solution. The solvent was removed undervacuum and the resulting hydrochloride salt was combined withdifluoroacetic acid (19.2 g, 0.18 mol) and 4 M HCl (100 mL). The mixturewas heated under reflux for 3 hrs, diluted with water, decolorized withcharcoal, and filtered through celite. Neutralization with aqueousammonia gave 2-difluoromethyl-4-methoxy-1H-benzimidazole (15.2 g, 84%)as a solid: ¹H NMR (CDCl₃) (tautomeric mixture) δ 9.95-9.70 (m,exchangeable with D₂O, 1H), 7.44 (br d, J=7.9 Hz, 0.4H), 7.31-7.24 (m,1H), 7.12 (br d, J=8.0 Hz, 0.5H), 6.89 (t, J_(HF)=53.8 Hz, 1H),6.82-6.74 (m, 1H), 4.03 and 3.98 (2s, 3H).

A mixture of 3.96 g (20 mmol) of2-difluoromethyl-4-methoxy-1H-benzimidazole, 4.70 g (20 mmol) of2,4-dichloro-6-(4-morpholinyl)-1,3,5-triazine, and 22 g (80 mmol) ofpowdered K₂CO₃ in 150 mL of DMF was stirred rapidly for 3 hrs, and thendiluted with water. The resulting precipitate was collected, washed withwater and then with cold ethanol, and dried to give 6.82 g (86%) of1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole:mp (CHCl₃/EtOH) 263-266° C.; ¹H NMR (CDCl₃) δ 7.99 (d, J=8.4 Hz, 1H),7.48 (t, J_(HF)=53.4 Hz, 1H), 7.40 (t, J=8.3 Hz, 1H), 6.86 (d, J=8.1 Hz,1H), 4.05 (s, 3H), 3.96 (m, 4H), 3.82 (m, 4H); Anal. Calcd. forC₁₆H₁₅ClF₂N₆O₂: C, 48.4; H, 3.8; N, 21.2. Found: C, 48.3; H, 3.8; N,21.1%.

A mixture of 1.98 g (5 mmol) of1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole,1.16 g (6.25 mmol) of tert-butyl 1-piperazinecarboxylate, and 1.29 g (10mmol) of DIPEA in 100 mL of THF was stirred at room temperature for 1hr, and the solution was concentrated under vacuum. The residue wasdiluted with water (100 mL) containing 1 mL of acetic acid. Theresulting precipitate was collected, washed with water, and dried togive 2.71 g (99% yield) of tert-butyl4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinecarboxylate:mp (MeOH) 221-223° C.; ¹H NMR (CDCl₃) δ 7.88 (dd, J=8.4, 0.6 Hz, 1H),7.47 (t, J=53.5 Hz, 1H), 7.35 (t, J=8.2 Hz, 1H), 6.81 (d, J=7.7 Hz, 1H),4.05 (s, 3H), 3.87 (m, 8H), 3.78 (m, 4H), 3.53 (m, 4H), 1.50 (s, 9H);Anal. Calcd. for C₂₅H₃₂F₂N₈O₄: C, 54.9; H, 5.9; N, 20.5. Found: C, 54.9;H, 5.9; N, 20.5%.

Reaction of tert-butyl4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinecarboxylatefrom the previous step with an excess of TFA (10 mL) in CH₂Cl₂ (50 mL)at room temperature for 2 hrs, followed by treatment with aq. NH₃ gave2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazolein 100% yield: mp (EtOH) 228-231° C.: ¹H NMR (CDCl₃) δ 7.90 (d, J=7.9Hz, 1H), 7.50 (t, J_(HF)=53.5 Hz, 1H), 7.34 (t, J=8.3 Hz, 1H), 6.81 (d,J=7.8 Hz, 1H), 4.05 (s, 3H), 3.87 (m, 8H), 3.78 (m, 4H), 2.95 (m, 4H);Anal. Calcd. for C₂₀H₂₄F₂N₈O₂: C, 53.8; H, 5.4; N, 25.1. Found: C, 53.8;H, 5.6; N, 25.3%.

A solution of 107 mg (0.24 mmol) of2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazolein a mixture of 20 mL of THF and 20 mL of pyridine was cooled to 0° C.and 41 mg (0.36 mmol) of methanesulfonyl chloride was added. The mixturewas allowed to warm to room temperature, and after 1 hr, water wasadded. The precipitate was collected, washed with water, and dried togive 95 mg (75% yield) of2-(difluoromethyl)-4-methoxy-1-[4-[4-(methylsulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole:mp (MeOH) 311-314° C.; ¹H NMR (CDCl₃) δ 7.86 (dd, J=8.4, 0.6 Hz, 1H),7.43 (t, J_(HF)=53.5 Hz, 1H), 7.36 (t, J=8.2 Hz, 1H), 6.82 (d, J=7.8 Hz,1H), 4.05 (s, 3H), 4.03 (m, 4H), 3.89 (m, 4H), 3.79 (m, 4H), 3.33 (m,4H), 2.81 (s, 3H); Anal. Calcd. for C₂₁H₂₆F₂N₈O₄S: C, 48.1; H, 5.0; N,21.4. Found: C, 48.0; H, 4.9; N, 21.2%.

Example 3 Synthesis of2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(vinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole

A solution of 0.224 g (0.5 mmol) of2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole(Example 2) and 25 mg of DMAP in 10 mL of pyridine was cooled to 0° C.and 0.122 g (0.75 mmol) of 2-chloroethanesulfonyl chloride was addeddropwise over 5 min. The mixture was stirred at 0° C. for 2 hrs andwater was added to give a precipitate which was collected and dried.Chromatography on silica eluting with CH₂Cl₂/EtOAc (4:1) gave 183 mg(31% yield) of2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(vinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole:mp (MeOH) 242-244° C.; ¹H NMR (CDCl₃) δ 7.85 (dd, J=8.4, 0.7 Hz, 1H),7.43 (t, J_(HF)=53.5 Hz, 1H), 7.35 (t, J=8.2 Hz, 1H), 6.82 (d, J=7.7 Hz,1H), 6.43 (dd, J=16.6, 9.8 Hz, 1H), 6.29 (d, J=16.6 Hz, 1H), 6.07 (d,J=9.8 Hz, 1H), 4.05 (s, 3H), 4.01 (m, 4H), 3.87 (m, 4H), 3.78 (m, 4H),3.26 (m, 4H); MS (APCI⁺) m/z 538.4; Anal. Calcd. for C₂₂H₂₆F₂N₈O₄S: C,49.25; H, 4.9; N, 20.9. Found: C, 49.1; H, 5.0; N, 20.4%.

Example 4 Synthesis ofN-[3-({2-(difluoromethyl)-1-[4-[4-(methylsulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazol-4-yl}oxy)propyl]-N,N-dimethylamine

Reaction of4-(tert-butyldimethylsilyloxy)-2-(difluoromethyl)-1H-benzimidazole with2,4-dichloro-6-(4-morpholinyl)-1,3,5-triazine as in Example 2, but usingacetone as solvent, followed by chromatography on silica gel elutingwith CH₂Cl₂/hexanes 3:1 gave4-(tert-butyldimethylsilyloxy)-1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole:mp (hexanes) 143-145° C.; ¹H NMR (CDCl₃) δ 7.99 (d, J=8.4 Hz, 1H), 7.46(t, J_(HF)=53.5 Hz, 1H), 7.32 (t, J=8.2 Hz, 1H), 6.88 (d, J=8.0 Hz, 1H),3.96 (m, 3.5H), 3.88 (m, 0.5H), 3.81 (m, 3.5H), 3.75 (m, 0.5H), 1.05 (s,9H), 0.29 (s, 6H); MS (APCI⁺) 497.9/499.9 MH⁺. Anal. Calcd. forC₂₁H₂₇ClF₂N₆O₂Si: C, 50.75; H, 5.5; N, 16.9. Found: C, 50.7; H, 5.6; N,17.0%.

Reaction of4-(tert-butyldimethylsilyloxy)-1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazolewith 2.2 equivalents of tert-butyl 1-piperazinecarboxylate in THF atroom temperature gave a quantitative yield of tert-butyl4-[4-[4-(tert-butyldimethylsilyloxy)-2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]piperazine-1-carboxylateas an oil: ¹H NMR (CDCl₃) 7.91 (d, J=8.2 Hz, 1H), 7.45 (t, J_(HF)=53.6Hz, 1H), 7.26 (t, J=8.1 Hz, 1H), 6.83 (d, J=7.9 Hz, 1H), 3.85 (m, 8H),3.77 (m, 4H), 3.53 (m, 4H), 1.50 (s, 9H), 1.05 (s, 9H), 0.30 (s, 6H); MS(APCI⁺) 648.7 [MH⁺].

Reaction of tert-butyl4-[4-[4-(tert-butyldimethylsilyloxy)-2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]piperazine-1-carboxylatefrom the previous step with tetrabutylammonium fluoride in THF at 0° C.gave a quantitative yield of tert-butyl4-[4-[2-(difluoromethyl)-4-hydroxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]piperazine-1-carboxylate:mp (MeOH) 228-230° C.; ¹H NMR (CDCl₃) δ 7.81 (d, J=8.4 Hz, 1H), 7.55 (t,J_(HF)=53.6 Hz, 1H), 7.32 (t, J=8.2 Hz, 1H), 6.90 (d, J=8.0 Hz, 1H),3.88 (m, 8H), 3.79 (m, 4H), 3.53 (m, 4H), 1.50 (s, 9H); MS (APCI⁺) 534.1[MH⁺]; Anal. Calcd. for C₂₄H₃₀F₂N₈O₄: C, 54.1; H, 5.7; N, 21.0. Found:C, 54.15; H, 5.8; N, 21.3%.

A mixture of 0.60 g (1.1 mmol) of tert-butyl4-[4-[2-(difluoromethyl)-4-hydroxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]piperazine-1-carboxylate,0.47 g (3.3 mmol) of 3-bromo-1-propanol, and 0.80 g (5.5 mmol) ofpowdered K₂CO₃ in 20 mL dry DMF was stirred at room temperature for 8hrs. Dilution with water gave 0.66 g, (99% yield) of tert-butyl4-[4-[2-(difluoromethyl)-4-(3-hydroxypropoxy)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinecarboxylate:¹H NMR (CDCl₃) δ 7.94 (dd, J=8.4. 0.7 Hz, 1H), 7.49 (t, J_(HF)=53.4 Hz,1H), 7.34 (t, J=8.1 Hz, 1H), 6.92 (dd, J=8.0, 0.6 Hz, 1H), 4.47 (t,J=5.9 Hz, 2H), 3.98 (t, J=5.4 Hz, 2H), 3.87 (m, 8H), 3.79 (m, 4H), 3.54(m, 4H), 3.30 (m, exchangeable with D₂O, 1H), 2.14 (pentet, J=5.8 Hz,2H), 1.50 (s, 9H).

A mixture of tert-butyl4-[4-[2-(difluoromethyl)-4-(3-hydroxypropoxy)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinecarboxylatefrom the previous step and 0.34 g (3.3 mmol) of Et₃N in 20 mL of THF wascooled to 0° C. and 0.32 g (2.8 mmol) of methanesulfonyl chloride wasadded dropwise. After 1 hr, 6 g of 40% aqueous Me₂NH was added, and theresulting mixture was stirred at room temperature for 36 hrs. The THFwas removed under vacuum and the residue was diluted with water andextracted into CH₂Cl₂. Drying and removal of the solvent gave tert-butyl4-[4-{2-(difluoromethyl)-4-[3-(dimethylamino)propoxy]-1H-benzimidazol-1-yl}-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinecarboxylateas an oil: ¹H NMR (CDCl₃) δ 7.87 (dd, J=8.4. 0.6 Hz, 1H), δ 7.48 (t,J_(HF)=53.5 Hz, 1H), 7.33 (t, J=8.2 Hz, 1H), 6.85 (d, J=7.8 Hz, 1H),4.31 (t, J=6.7 Hz, 2H), 3.87 (m, 8H), 3.79 (m, 4H), 3.53 (m, 4H), 2.51(t, J=7.2 Hz, 2H), 2.26 (s, 6H), 2.13 (pentet, J=7.0 Hz, 2H), 1.50 (s,9H).

Treatment of tert-butyl4-[4-{2-(difluoromethyl)-4-[3-(dimethylamino)propoxy]-1H-benzimidazol-1-yl}-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinecarboxylatefrom the previous step with TFA in CH₂Cl₂ gaveN-[3-({2-(difluoromethyl)-1-[4-(4-morpholinyl)-6-(1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazol-4-yl}oxy)propyl]-N,N-dimethylamineas a solid: ¹H NMR (CDCl₃) δ 7.89 (dd, J=8.4. 0.7 Hz, 1H), 7.50 (t,J_(HF)=53.5 Hz, 1H), 7.31 (t, J=8.2 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H),4.32 (t, J=6.8 Hz, 2H), 3.86 (m, 8H), 3.78 (m, 4H), 2.95 (m, 4H), 2.53(t, J=7.2 Hz, 2H), 2.27 (s, 6H), 2.13 (pentet, J=6.9 Hz, 2H).

A stirred mixture of 297 mg (0.57 mmol) ofN-[3-({2-(difluoromethyl)-1-[4-(4-morpholinyl)-6-(1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazol-4-yl}oxy)propyl]-N,N-dimethylamineand 1 g of powdered K₂CO₃ in CH₂Cl₂ was cooled to 0° C. and 0.4 g ofmethanesulphonyl chloride was added. The mixture was allowed to warm toroom temperature, and after 2 hrs it was diluted with water and theorganic layer was separated and dried. Chromatography on alumina,eluting first with CH₂Cl₂/EtOAc (1:1) and then with EtOAc gave 200 mg(59% yield) ofN-[3-({2-(difluoromethyl)-1-[4-[4-(methylsulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazol-4-yl}oxy)propyl]-N,N-dimethylamine:¹H NMR (CDCl₃) δ 7.84 (dd, J=8.4. 0.6 Hz, 1H), 7.43 (t, J_(HF)=53.5 Hz,1H), 7.33 (t, J=8.2 Hz, 1H), 6.86 (d, J=7.7 Hz, 1H), 4.32 (t, J=6.8 Hz,2H), 4.02 (m, 4H), 3.88 (m, 4H), 3.78 (m, 4H), 3.33 (m, 4H), 2.81 (s,3H), 2.54 (t, J=7.2 Hz, 2H), 2.28 (s, 6H), 2.14 (pentet, J=7.0 Hz, 2H);Hydrochloride: mp (EtOH) 243-247° C.; Anal. Calcd. for C₂₅H₃₆ClF₂N₉O₄S1.5H₂O: C, 45.6; H, 6.0; Cl, 5.4, N, 19.1. Found: C, 45.5; H, 6.1; Cl,5.2; N, 19.2%.

Example 5 Synthesis of4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-methyl-N-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine

A mixture of 0.397 g (1 mmol) of1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole(Example 2), 0.24 g (1.2 mmol) of tert-butyl4-amino-1-piperidinecarboxylate, and 0.194 g (1.5 mmol) of DIPEA in 25mL of THF was stirred at room temperature overnight. Dilution with waterand extraction with CH₂Cl₂, followed by chromatography on silica elutingwith CH₂Cl₂/EtOAc (4:1) gave 0.51 g (91% yield) of tert-butyl4-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}-1-piperidinecarboxylate:mp (hexanes/CH₂Cl₂) 142-145° C.; ¹H NMR (CDCl₃) (rotamer mixture; ratioca. 3:2) δ 7.96 and 7.95 (2d, J=8.3 and 7.9 Hz, 1H), 7.54 and 7.52 (2t,J_(HF)=53.6 Hz, 1H), 7.34 (br t, J=8.1 Hz, 1H), 6.81 (t, J=6.9 Hz, 1H),5.22 and 5.17 (2d, J=7.4 and 7.6 Hz, exchangeable with D₂O, 1H), 4.10(m, 3H), 4.05 (s, 3H), 3.87 (m, 4H), 3.78 (m, 4H), 2.93 (t, J=12.1 Hz,2H) 2.06 (m, 2H), 1.48 (s, 9H), 1.43 (m, 2H); Anal. Calcd. forC₂₆H₃₄F₂N₈O₄: C, 55.7; H, 6.1; N, 20.0. Found: C, 55.6; H, 6.2; N,20.0%.

A solution of 0.30 g (5.4 mmol) of tert-butyl4-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}-1-piperidinecarboxylatein 10 mL of DMF was treated sequentially with excess NaH and iodomethaneat room temperature for 2 hrs. Dilution with water and workup in CH₂Cl₂,followed by chromatography on silica eluting with CH₂Cl₂/EtOAc (4:1)gave 0.286 g (93% yield) of tert-butyl4-[[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl](methyl)amino]-1-piperidinecarboxylate:mp (MeOH/CH₂Cl₂) 200-202° C.; ¹H NMR (CDCl₃) (rotamer mixture; ratio ca.3:2) δ 7.98 and 7.91 (2d, J=8.4 Hz, 1H), 7.57 and 7.47 (2t, J_(HF)=53.5Hz, 1H), 7.34 (t, J=8.2 Hz, 1H), 6.81 (d, J=7.9 Hz, 1H), 4.82 and 4.70(2m, 1H), 4.29 (m, 2H), 4.05 (s, 3H), 3.88 (m, 4H), 3.79 (m, 4H), 3.10and 3.05 (2s, 3H), 2.84 (m, 2H), 1.73 (m, 4H), 1.49 (s, 9H); Anal.Calcd. for C₂₇H₃₆F₂N₈O₄: C, 56.4; H, 6.3; N, 19.5. Found: C, 56.6; H,6.4; N, 19.6%.

Treatment of 0.173 g (0.3 mmol) of tert-butyl4-[[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl](methyl)amino]-1-piperidinecarboxylatewith TFA in CH₂Cl₂ at room temperature gave 0.143 g (100% yield) ofcrude4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-methyl-6-(4-morpholinyl)-N-(4-piperidinyl)-1,3,5-triazin-2-amine:¹H NMR (CDCl₃) (rotamers; ratio ca. 3:2) δ 7.99 and 7.94 (2d, J=8.4 Hz,1H), 7.59 and 7.52 (2t, J_(HF)=53.6 Hz, 1H), 7.34 (t, J=8.2 Hz, 1H),6.81 (d, J=8.0 Hz, 1H), 4.80-4.63 (m, 1H), 4.06 (s, 3H), 3.88 (m, 4H),3.79 (m, 4H), 3.25 (m, 2H), 3.13 and 3.09 (2s, 3H), 2.88-2.73 (m, 2H),1.98-1.72 (m, 4H), 1.49 (s, 9H).

Reaction of4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-methyl-6-(4-morpholinyl)-N-(4-piperidinyl)-1,3,5-triazin-2-aminefrom the previous step with methanesulphonyl chloride as in Example 4gave4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-methyl-N-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-aminein 56% yield: mp (CH₂Cl₂/MeOH) 190-192° C.; ¹H NMR (DMSO-d₆) (rotamers)δ 7.97 and 7.89 (2d, J=8.3, 8.5 Hz, 1H), 7.69 and 7.74 (2t, J_(HF)=52.9Hz, 1H), 7.46-7.39 (m, 1H), 6.95 (d, J=7.8 Hz, 1H), 4.69-4.61 (m, 1H),3.98 (s, 3H), 3.80-3.69 (m, 10H), 3.09 and 2.95 (2s, 3H), 2.93-2.92 (2s,3H), 2.92-2.78 (m, 2H), 1.93-1.67 (m, 4H); Anal. Calcd. forC₂₃H₃₀F₂N₈O₄S: C, 50.0, H, 5.5, N, 20.3. Found: C, 49.5, H, 5.3; N,20.0%.

Example 6 Synthesis of2-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-methyl-N-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-4-pyrimidinamine

A mixture of 95 mg (2 mmol) of2-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-methyl-6-(4-morpholinyl)-N-(4-piperidinyl)-4-pyrimidinamineand 61 mg (6 mmol) of Et₃N in 15 mL THF was cooled to 0° C. and 46 mg (4mmol) of methanesulphonyl chloride was added. The stirred mixture wasallowed to warm to room temperature, and after 2 hrs it was diluted withwater to give a precipitate of 98 mg (89% yield) of2-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-methyl-N-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-4-pyrimidinamine:mp (MeOH) 191-193° C.; ¹H NMR (CDCl₃) δ 7.77 (dd, J=8.4. 0.6 Hz, 1H),7.37 (t, J_(HF)=53.4 Hz, 1H), 7.31 (t, J=8.2 Hz, 1H), 6.79 (d, J=7.6 Hz,1H), 5.40 (s, 1H), 4.96 (m, 1H), 4.05 (s, 3H), 3.99-3.93 (m, 2H), 3.83(m, 4H), 3.64 (m, 4H), 2.90 (s, 3H), 2.82 (s, 3H), 2.81 (dt, J=12.0, 2.4Hz, 2H), 1.91 (dq J=12.3, 4.3 Hz, 2H), 1.85-1.76 (m, 2H); Anal. Calcd.for C₂₄H₃₁F₂N₇O₄S: C, 52.3; H, 5.7; N, 17.8. Found: C, 52.5; H, 5.7; N,17.9%.

Example 7 Synthesis ofN-[3-({2-(difluoromethyl)-1-[4-{[1-(methylsulfonyl)-4-piperidinyl]oxy}-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazol-4-yl}oxy)propyl]-N,N-dimethylamine

A mixture of 0.60 g (1.1 mmol) of tert-butyl4-[4-[2-(difluoromethyl)-4-hydroxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]piperazine-1-carboxylate(Example 5), 0.47 g (3.3 mmol) of 3-bromo-1-propanol, and 0.80 g (5.5mmol) of powdered K₂CO₃ in 20 mL dry DMF was stirred at room temperaturefor 8 hrs. Dilution with water, filtration, and dry gave 0.66 g (99%yield) of tert-butyl4-[4-[2-(difluoromethyl)-4-(3-hydroxypropoxy)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinecarboxylate:¹H NMR (CDCl₃) δ 7.94 (dd, J=8.4. 0.7 Hz, 1H), 7.49 (t, J_(HF)=53.4 Hz,1H), 7.34 (t, J=8.1 Hz, 1H), 6.92 (dd, J=8.0, 0.6 Hz, 1H), 4.47 (t,J=5.9 Hz, 2H), 3.98 (t, J=5.4 Hz, 2H), 3.87 (m, 8H), 3.79 (m, 4H), 3.54(m, 4H), 3.30 (m, exchangeable with D₂O, 1H), 2.14 (pentet, J=5.8 Hz,2H), 1.50 (s, 9H).

A mixture of tert-butyl4-[4-[2-(difluoromethyl)-4-(3-hydroxypropoxy)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinecarboxylatefrom the previous step and 0.34 g (3.3 mmol) of Et₃N in 20 mL of THF wascooled to 0° C. and 0.32 g (2.8 mmol) of methanesulfonyl chloride wasadded dropwise. After 1 hr, 6 g of 40% aqueous Me₂NH was added, and theresulting mixture was stirred at room temperature for 36 hrs. The THFwas removed under vacuum and the residue was diluted with water andextracted into CH₂Cl₂. Drying and removal of the solvent gave tert-butyl4-[4-{2-(difluoromethyl)-4-[3-(dimethylamino)propoxy]-1H-benzimidazol-1-yl}-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinecarboxylateas an oil: ¹H NMR (CDCl₃) δ 7.87 (dd, J=8.4. 0.6 Hz, 1H), 7.48 (t,J_(HF)=53.5 Hz, 1H), 7.33 (t, J=8.2 Hz, 1H), 6.85 (d, J=7.8 Hz, 1H),4.31 (t, J=6.7 Hz, 2H), 3.87 (m, 8H), 3.79 (m, 4H), 3.53 (m, 4H), 2.51(t, J=7.2 Hz, 2H), 2.26 (s, 6H), 2.13 (pentet, J=7.0 Hz, 2H), 1.50 (s,9H).

Treatment of tert-butyl4-[4-{2-(difluoromethyl)-4-[3-(dimethylamino)propoxy]-1H-benzimidazol-1-yl}-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinecarboxylatefrom the previous step with TFA in CH₂Cl₂ gaveN-[3-({2-(difluoromethyl)-1-[4-(4-morpholinyl)-6-(1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazol-4-yl}oxy)propyl]-N,N-dimethylamineas a solid: ¹H NMR (CDCl₃) δ 7.89 (dd, J=8.4. 0.7 Hz, 1H), 7.50 (t,J_(HF)=53.5 Hz, 1H), 7.31 (t, J=8.2 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H),4.32 (t, J=6.8 Hz, 2H), 3.86 (m, 8H), 3.78 (m, 4H), 2.95 (m, 4H), 2.53(t, J=7.2 Hz, 2H), 2.27 (s, 6H), 2.13 (pentet, J=6.9 Hz, 2H).

Reaction ofN-[3-({2-(difluoromethyl)-1-[4-(4-morpholinyl)-6-(1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazol-4-yl}oxy)propyl]-N,N-dimethylaminefrom the previous step with methanesulphonyl chloride and powdered K₂CO₃in CH₂Cl₂, followed by chromatography on alumina eluting withCH₂Cl₂/EtOAc (1:1) g, and acidification with HCl in MeOH gaveN-[3-({2-(difluoromethyl)-1-[4-{[1-(methylsulfonyl)-4-piperidinyl]oxy}-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazol-4-yl}oxy)propyl]-N,N-dimethylaminehydrochloride in 71% yield: ¹H NMR (DMSO-d₆) δ 10.07 (br s, exchangeablewith D₂O, 1H), 7.99 (d, J=8.2 Hz, 1H), 7.73 (t, J_(HF)=52.7 Hz, 1H),7.46 (t, J=8.2 Hz, 1H), 7.02 (d, J=8.0 Hz, 1H), 5.27-5.21 (m, 1H), 4.34(t, J=6.1 Hz, 2H), 3.86-3.85 (m, 4H), 3.74-3.71 (m, 4H), 3.44-3.38 (m,2H), 3.20-3.14 2.93 (s, 3H), 2.82 (s, 6H), (m 2H), 2.28-2.26 (m, 2H),2.15-2.10 (m, 2H); Anal. Calcd. for C₂₆H₂₉ClF₂N₈O₅S.0.75 H₂O: C, 47.3;H, 5.9; Cl, 5.4; N, 17.0. Found: C, 47.3; H, 5.8; Cl, 5.4; N, 17.0%.

Example 8 Synthesis of6-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-1-[1-(methylsulfonyl)-4-piperidinyl]-4-(4-morpholinyl)-1H-pyrazolo[3,4-d]pyrimidine

A stirred mixture of 0.44 g (2.2 mmol) of2-(difluoromethyl)-4-methoxy-1H-benzimidazole, 0.47 g (1.1 mmol) oftert-butyl4-[6-chloro-4-(4-morpholinyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinecarboxylate(WO 2008/115974), and 0.61 g (4.4 mmol) of powdered K₂CO₃ in 10 mL ofDMSO was heated at 160° C. for 20 hrs. After cooling, the mixture wasdiluted with water, and the precipitate was collected by filtration,washed with water, and dried. Chromatography on silica eluting withCH₂Cl₂/EtOAc (17:3) gave 0.20 g (31% yield) of tert-butyl4-[6-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-4-(4-morpholinyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinecarboxylate:mp (MeOH) 245-247° C.; ¹H NMR (CDCl₃) δ 7.99 (s, 1H), 7.84 (dd, J=8.4,0.6 Hz, 1H), 7.47 (t, J_(HF)=53.6 Hz, 1H), 7.37 (t, J=8.2 Hz, 1H), 6.83(d, J=7.8 Hz, 1H), 4.87 (tt, J=11.4, 4.1 Hz, 1H), 4.32 (m, 2H), 4.07 (s,3H), 4.06 (m, 4H), 3.91 (m, 4H), 2.99 (m, 2H), 2.23 (dq, J=12.3, 4.5 Hz,2H), 2.02 (m, 2H), 1.49 (s, 9H); Anal. Calcd. for C₂₈H₃₄F₂N₈O₄: C, 57.5;H, 5.9; N, 19.2. Found: C, 57.2; H, 6.0; N, 19.0%.

Treatment of tert-butyl4-[6-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-4-(4-morpholinyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinecarboxylatefrom the previous step with TFA in CH₂Cl₂ at room temperature gave6-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-4-(4-morpholinyl)-1-(4-piperidinyl)-1H-pyrazolo[3,4-d]pyrimidinein 97% yield: ¹H NMR (CDCl₃) δ 8.00 (s, 1H), 7.86 (dd, J=8.4, 0.6 Hz,1H), 7.51 (t, J_(HF)=53.6 Hz, 1H), 7.38 (t, J=8.2 Hz, 1H), 6.83 (d,J=7.7 Hz, 1H), 4.83 (tt, J=11.6, 4.1 Hz, 1H), 4.07 (s, 3H), 4.06 (m,4H), 3.91 (m, 4H), 3.31 (m, 2H), 2.87 (dt, J=12.7, 2.5 Hz, 2H), 2.21(dq, J=12.3, 4.2 Hz, 2H), 2.04 (m, 2H).

A mixture of 75 mg (155 mmol) of6-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-4-(4-morpholinyl)-1-(4-piperidinyl)-1H-pyrazolo[3,4-d]pyrimidineand 65 mg (465 mmol) of powdered K₂CO₃ in CH₂Cl₂ was cooled to 0° C.,and 27 mg (233 mmol) of methanesulfonyl chloride was added. The mixturewas allowed to warm to room temperature, and after 2 hrs it was dilutedwith water and washed with aq. NH₃. The organic layer was dried (Na₂SO₄)and concentrated under vacuum to give 80 mg (92% yield) of6-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-1-[1-(methylsulfonyl)-4-piperidinyl]-4-(4-morpholinyl)-1H-pyrazolo[3,4-d]pyrimidine:mp (MeOH) 273-276° C.; ¹H NMR (CDCl₃) δ 8.01 (s, 1H), 7.82 (dd, J=8.4,0.6 Hz, 1H), 7.46 (t, J=53.6 Hz, 1H), 7.38 (t, J=8.2 Hz, 1H), 6.83 (d,J=7.8 Hz, 1H), 4.85 (tt, J=11.1, 4.1 Hz, 1H), 4.07 (s, 3H), 4.06 (m,4H), 4.02 (m, 1H), 3.99 (m, 1H), 3.92 (m, 4H), 3.02 (dt, J=12.2, 2.5 Hz,2H), 2.88 (s, 3H), 2.44 (dq, J=11.6, 4.2 Hz, 2H), 2.17 (m, 2H); Anal.Calcd. for C₂₄H₂₈F₂N₈O₄S: C, 51.2; H, 5.0; N, 19.9. Found: C, 50.85; H,5.0; N, 19.7%.

Example 9 Synthesis of2-(difluoromethyl)-4-methoxy-1-[4-[4-(methylsulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazol-6-ylamine

A mixture of 2,3-diamino-5-nitroanisole (Horner et al., Annalen 1953,579, 212) (1.10 g, 6 mmol) and difluoroacetic acid (2.31 g, 24 mmol) inpolyphosphoric acid (PPA) (50 g) was heated at 130° C. in an oil bathfor 1 hr. The hot solution was poured into water, and the pH wasadjusted to neutral with cooling to give2-(difluoromethyl)-4-methoxy-6-nitro-1H-benzimidazole (1.33 g, 91%): mp(EtOH/H₂O) 192-194° C.; ¹H NMR (DMSO-d₆) 814.18 (br, exchangeable withD₂O, 1H), 8.18 (br, 1H), 7.65 (dd, J=1.4 Hz, 1H), 7.30 (t, J_(HF)=52.9Hz, 1H), 4.07 (s, 3H); Anal. Calcd. for C₉H₇F₂N₃O₃: C, 44.45; H, 2.9; N,17.3. Found: C, 44.75; H, 3.0; N, 17.3%.

A solution of 2-(difluoromethyl)-4-methoxy-6-nitro-1H-benzimidazole(1.22 g, 5 mmol) in MeOH (50 mL) was hydrogenated over 10% Pd on C (50mg). After filtration to remove the catalyst Pd/C, the solution wasevaporated to dryness. The residue was combined with di-tert-butyldicarbonate (3.2 g, 15 mmol) in dioxane (20 mL), and the mixture washeated under reflux for 5 hrs. The solvent was removed under vacuum andthe residue was dissolved in MeOH (30 mL) containing aqueous NaOH (2 M,12.5 mL, 5 equiv.). The mixture was stirred at room temperature for 1hr, neutralized with HOAc, and evaporated to dryness. The residue wasextracted with EtOAc, washed with NaHCO₃ solution, and dried overNa₂SO₄. Chromatography on silica eluting with CH₂Cl₂/EtOAc (9:1) gave1.54 g (98% yield) of tert-butyl2-(difluoromethyl)-4-methoxy-1H-benzimidazol-6-yl-carbamate: mp (i-Pr₂O)189-191° C.; ¹H NMR (DMSO-d₆) δ 13.0 (br, exchangeable with D₂O, 1H),9.31 (br s, exchangeable with D₂O, 1H), 7.42 (br s, 1H), 7.15 (t,J_(HF)=53.4 Hz, 1H), 6.90 (br, 1H), 3.90 (s, 3H), 1.49 (s, 9H); Anal.Calcd. For C₁₄H₁₇F₂N₃O₃: C, 53.7; H, 5.5; N, 13.4. Found: C, 53.9; H,5.6; N, 13.4%.

A mixture of tert-butyl2-(difluoromethyl)-4-methoxy-1H-benzimidazol-6-yl-carbamate (0.47 g, 1.5mmol), 2,4-dichloro-6-(4-morpholinyl)-1,3,5-triazine (0.35 g, 1.5 mmol),and powdered K₂CO₃ (0.83 g, 6 mmol) in DMF (10 mL) was stirred at roomtemperature for 30 min. The reaction mixture was then diluted withwater. The resulting precipitate was collected, washed with water andthen MeOH, and dried to give 0.45 g (59% yield) of tert-butyl1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazol-6-yl-carbamate:mp (CH₂Cl₂/MeOH)>300° C.; ¹H NMR (CDCl₃) δ 8.45 (d, J=0.6 Hz, 1H), 7.57(t, J_(HF)=53.6 Hz, 1H), 6.67 (br, exchangeable with D₂O, 1H), 6.63 (d,J=0.9 Hz, 1H), 4.11 (m, 2H), 4.02 (s, 3H), 3.97 (m, 2H), 3.88 (m, 2H),3.82 (m, 2H), 1.52 (s, 9H); Anal. Calcd. for C₂₁H₂₄ClF₂N₇O₄: C, 49.3; H,4.7; N, 19.15. Found: C, 49.4; H, 4.8; N, 19.2%.

A mixture of tert-butyl1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazol-6-yl-carbamate(0.333 g, 0.65 mmol), 1-(methylsulfonyl)piperazine (0.32 g, 2 mmol), andDIPEA (0.17 g, 1.3 mmol) in THF (50 mL) was heated under reflux for 3hrs. The solution was concentrated and then diluted with 100 mL of watercontaining 1% HOAc to give a solid, which was collected and dried.Chromatography on silica eluting with CH₂Cl₂/EtOAc (4:1), followed byrecrystallization from MeOH, gave 0.33 g (79% yield) of tert-butyl2-(difluoromethyl)-4-methoxy-1-[4-[4-(methylsulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazol-6-ylcarbamate:mp 223° C. (decomp.); ¹H NMR (CDCl₃) δ 8.63 (br s, 1H), 7.44 (t,J_(HF)=53.6 Hz, 1H), 6.62 (br s, exchangeable with D₂O, 1H), 6.35 (d,J=1.7 Hz, 1H), 4.09-3.80 (m, 15H), 3.35 (m, 4H), 2.80 (s, 3H), 1.52 (s,9H); Anal. Calcd. for C₂₆H₃₅F₂N₉O₆S: C, 48.8; H, 5.5; N, 19.7. Found: C,48.9; H, 5.6; N, 19.9%.

A mixture of tert-butyl2-(difluoromethyl)-4-methoxy-1-[4-[4-(methylsulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazol-6-ylcarbamate(0.20 g, 0.31 mmol) and TFA (5 mL) in CH₂Cl₂ (20 mL) was stirred at roomtemperature for 2 hrs. The mixture was diluted with CH₂Cl₂ (100 mL) andwater (100 mL), and the aqueous layer was made basic with aqueous NH₃.The organic layer was dried and concentrated under vacuum.Recrystallization of the residue from CH₂Cl₂/MeOH gave 0.145 g (86%yield) of2-(difluoromethyl)-4-methoxy-1-[4-[4-(methylsulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazol-6-ylamine:mp 280-283° C.; ¹H NMR (CDCl₃) δ 7.59 (t, J_(HF)=53.4 Hz, 1H), 7.05 (d,J=1.7 Hz, 1H), 6.26 (d, J=1.7 Hz, 1H), 5.45 (s, exchangeable with D₂O,2H), 3.93 (m, 4H), 3.87 (s, 3H), 3.80 (m, 4H), 3.69 (m, 4H), 3.24 (m,4H), 2.91 (s, 3H); Anal. Calcd. for C₂₁H₂₇F₂N₉O₄S: C, 46.75; H, 5.0; N,23.4. Found: C, 47.0; H, 5.2; N, 23.4%.

Example 10 Synthesis ofN-[2-({4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)ethyl]-N,N-dimethylamine

A mixture of2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(vinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole(Example 3) (0.536 g, 1 mmol) and 40% aqueous dimethylamine (10 mL) inTHF (200 mL) was warmed gently until a clear solution was obtained.After 15 min, the THF was removed under vacuum and the residue wasdiluted with water to giveN-[2-({4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)ethyl]-N,N-dimethylamine:¹H NMR (CDCl₃) δ 7.86 (dd, J=8.4, 0.6 Hz, 1H), 7.45 (t, J_(HF)=53.5 Hz,1H), 7.36 (t, J=8.2 Hz, 1H), 6.82 (d, J=7.8 Hz, 1H), 4.05 (s, 3H), 4.00(m, 4H), 3.89 (m, 4H), 3.79 (m, 4H), 3.39 (m, 4H), 3.11 (dd, J=8.1, 6.4Hz, 2H), 2.78 (dd, J=8.1, 6.4 Hz, 2H), 2.26 (s, 6H).

To a suspension ofN-[2-({4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)ethyl]-N,N-dimethylaminefrom the previous step in MeOH (100 mL) was added a slight excess of1.25 M HCl in MeOH (0.45 mL). The resulting clear solution wasconcentrated to dryness. The residue was recrystallized from MeOH/EtOActo give 0.51 g (83% yield for the last two steps) ofN-[2-({4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)ethyl]-N,N-dimethylaminehydrochloride: mp (MeOH/EtOAc) 222-224° C.; Anal. Calcd. forC₂₄H₃₄ClF₂N₉O₄S: C, 46.6; H, 5.5; N, 20.4; Cl, 5.7. Found: C, 46.3; H,5.7; N, 20.0; Cl, 5.7%.

Example 11 Synthesis of2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[2-(4-morpholinyl)ethyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole

A mixture of2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(vinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole(from Example 3) (0.536 g, 1 mmol) and morpholine (10 mL) in THF (150mL) was heated under reflux for 2 hrs. The solvent was removed undervacuum and the residue was diluted with water to give 0.605 g (97%yield) of2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[2-(4-morpholinyl)ethyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole:¹H NMR (CDCl₃) δ 7.86 (d, J=7.9 Hz, 1H), 7.44 (t, J_(HF)=53.5 Hz, 1H),7.36 (t, J=8.2 Hz, 1H), 6.83 (d, J=7.8 Hz, 1H), 4.05 (s, 3H), 4.00 (m,4H), 3.89 (m, 4H), 3.79 (m, 4H), 3.37 (m, 4H) 3.39 (m, 4H), 3.14 (dd,J=8.3, 6.4 Hz, 2H), 2.84 (dd, J=8.3, 6.3 Hz, 2H), 2.48 (m, 4H).

2-(Difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[2-(4-morpholinyl)ethyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazolehydrochloride was prepared according to the procedure as described inExample 10: mp (MeOH/EtOAc) 209-212° C.; Anal. Calcd. forC₂₆H₃₆ClF₂N₉O₅S.1.2H₂O: C, 45.8; H, 5.7; N, 18.5; Cl, 5.2. Found: C,45.8; H, 5.7; N, 18.3; Cl, 5.2%.

Example 12 Synthesis of2-(difluoromethyl)-4-methoxy-1-[4-[4-({2-[4-(methylsulfonyl)-1-piperazinyl]ethyl}sulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole

A mixture of2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(vinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole(from Example 3) (0.20 g, 0.37 mmol) and 1-(methylsulfonyl)piperazine(0.31 g, 1.9 mmol) in THF (100 mL) was refluxed for 2 days. The solventwas then removed under vacuum, and the residue was diluted with water togive a white solid, which was collected and dried. Chromatography onalumina eluting with CH₂Cl₂/EtOAc (9:1) gave 0.22 g (84% yield) of2-(difluoromethyl)-4-methoxy-1-[4-[4-({2-[4-(methylsulfonyl)-1-piperazinyl]ethyl}sulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole:¹H NMR (CDCl₃) δ 7.86 (dd, J=8.4, 0.6 Hz, 1H), 7.43 (t, J_(HF)=53.5 Hz,1H), 7.35 (t, J=8.2 Hz, 1H), 6.82 (d, J=7.7 Hz, 1H), 4.05 (s, 3H), 4.01(m, 4H), 3.88 (m, 4H), 3.79 (m, 4H), 3.38 (m, 4H) 3.23 (m, 4H), 3.11(dd, J=8.5, 6.0 Hz, 2H), 2.92 (dd, J=8.4, 6.0 Hz, 2H), 2.75 (s, 3H),2.60 (m, 4H).

A suspension of2-(difluoromethyl)-4-methoxy-1-[4-[4-({2-[4-(methylsulfonyl)-1-piperazinyl]ethyl}sulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazolefrom the previous step in MeOH (50 mL) was treated with methanesulfonicacid (33 mg, 1.1 equiv.) to give a clear solution. The solvent wasremoved under vacuum and the residue was washed with EtOAc to give2-(difluoromethyl)-4-methoxy-1-[4-[4-({2-[4-(methylsulfonyl)-1-piperazinyl]ethyl}sulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazolemethanesulfonate: mp (MeOH/EtOAc) 232-235° C.; Anal. Calcd. forC₂₈H₄₂F₂N₁₀O₉S₃.0.5H₂O: C, 41.7; H, 5.4; N, 17.4. Found: C, 41.7; H,5.3; N, 17.2%.

Example 13 Synthesis of2-(difluoromethyl)-4-methoxy-1-[4-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole

A mixture of1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole(0.397 g, 1 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate(0.464 g, 1.5 mmol), PdCl₂(dppf) (56 mg), and 2 M Na₂CO₃ solution (8 mL)in dioxane (40 mL) was refluxed under nitrogen for 2 hrs. The dioxanewas removed under vacuum and the residue was extracted into CH₂Cl₂.Chromatography on silica eluting with CH₂Cl₂/EtOAc (95:5) gave 0.51 g(94% yield) of tert-butyl4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3,6-dihydro-1(2H)-pyridinecarboxylate:mp (MeOH) 223-225° C.; ¹H NMR (CDCl₃) δ 8.00 (dd, J=8.4, 0.6 Hz, 1H),7.56 (t, J_(HF)=53.5 Hz, 1H), 7.39 (t, J=8.2 Hz, 1H), 7.38 (m, 1H), 6.85(d, J=7.7 Hz, 1H), 4.23 (br d, J=3.0 Hz, 2H), 4.06 (s, 3H), 4.01 (m,2H), 3.95 (m, 2H), 3.82 (m, 4H), 3.65 (t, J=5.7 Hz, 2H), 2.69 (m, 2H),1.54-1.45 (m, 2H), 1.50 (s, 9H); Anal. Calcd. for C₂₆H₃₁F₂N₇O₄: C,57.45; H, 5.75; N, 18.0. Found: C, 57.4; H, 5.9; N, 18.15%.

A solution of tert-butyl4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3,6-dihydro-1(2H)-pyridinecarboxylate(1.79 g, 3.29 mmol) in a mixture of MeOH (80 mL) and THF (80 mL) washydrogenated over 10% Pd on carbon (100 mg). After removal of thehydrogen, the mixture was refluxed in air for additional 2 hrs. Thecatalyst Pd/C was removed by filtration through celite, and the solventswere removed under vacuum. Recrystallization of the residue frommethanol gave tert-butyl4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperidine-carboxylate:mp (MeOH) 177-179° C.; ¹H NMR (CDCl₃) δ 8.01 (dd, J=8.4, 0.7 Hz, 1H),7.58 (t, J_(HF)=53.6 Hz, 1H), 7.38 (t, J=8.2 Hz, 1H), 6.84 (d, J=7.8 Hz,1H), 4.22 (m, 2H), 4.05 (s, 3H), 3.99 (m, 2H), 3.94 (m, 2H), 3.81 (m,4H), 2.94-2.78 (m, 3H), 2.05 (dd, J=13.0, 1.9 Hz, 2H), 1.81 (qd, J=12.7,4.4 Hz, 2H), 1.49 (s, 9H); Anal. Calcd. for C₂₆H₃₃F₂N₇O₄: C, 57.2; H,6.1; N, 18.0. Found: C, 57.4; H, 6.15; N, 18.1%.

Reaction of tert-butyl4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperidine-carboxylate(0.23 g, 0.37 mmol) with TFA (0.45 mL) in CH₂Cl₂ (8 mL) gave2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-piperidinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole,which was treated subsequently with methanesulfonyl chloride and Et₃N inCH₂Cl₂. The reaction mixture was purified by chromatography on silicaeluting first with hexanes/EtOAc (1:1) and then hexanes/EtOAc (3:5) togive 0.13 g (67% yield) of2-(difluoromethyl)-4-methoxy-1-[4-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole:mp 256-258° C.; ¹H NMR (CDCl₃) δ 7.99 (dd, J=8.4, 0.7 Hz, 1H), 7.55 (t,J_(HF)=53.6 Hz, 1H), 7.39 (t, J=8.3 Hz, 1H), 6.85 (d, J=8.1 Hz, 1H),4.06 (s, 3H), 4.02-3.89 (m, 6H), 3.87-3.76 (m, 4H), 2.92-2.75 (m, 6H),2.24-2.16 (m, 2H), 2.10-1.97 (m, 2H); Anal. Calcd. for C₂₂H₂₇F₂N₇O₄S: C,50.5; H, 5.2; N, 18.7. Found: C, 50.6; H, 5.3; N, 18.6%.

Example 14 Synthesis ofN-[2-({4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperidinyl}sulfonyl)ethyl]-N,N-dimethylamine

To a mixture of2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-piperidinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole(Example 13) (0.891 mg, 2 mmol) and DIPEA (0.77 g, 6 mmol) in CH₂Cl₂(100 mL) was added dropwise 2-chloroethanesulfonyl chloride (0.49 g, 3mmol) at 0° C. After addition, the reaction mixture was stirred at 0° C.for additional 2 hrs. The reaction mixture was quenched with water (100mL). The organic layer was washed successively with aqueous HOAc (1%,100 mL) and aqueous NH₃, and dried. Chromatography on silica elutingwith CH₂Cl₂/EtOAc (9:1) gave 0.589 g (55% yield) of2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[1-(vinylsulfonyl)-4-piperidinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole:mp (MeOH) 229-232° C.; ¹H NMR (CDCl₃) δ 7.99 (dd, J=8.4, 0.7 Hz, 1H),7.54 (t, J_(HF)=53.6 Hz, 1H), 7.39 (t, J=8.3 Hz, 1H), 6.85 (d, J=7.6 Hz,1H), 6.47 (dd, J=16.6, 9.9 Hz, 1H), 6.27 (d, J=16.6 Hz, 1H), 6.05 (d,J=9.9 Hz, 1H), 4.06 (s, 3H), 4.00-3.97 (m, 4H), 3.89-3.79 (m, 6H), 2.78(m, 3H), 2.17 (br dd, J=13.6, 3.0 Hz, 2H), 2.01 (ddd, J=25.2, 11.7, 4.1Hz, 2H); Anal. Calcd. for C₂₃H₂₇F₂N₇O₄S: C, 51.6; H, 5.1; N, 18.3.Found: C, 51.7; H, 5.2; N, 18.25%.

A mixture of2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[1-(vinylsulfonyl)-4-piperidinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole(59 mg, 0.11 mmol) and 40% aqueous dimethylamine (5 mL) in THF (25 mL)was stirred at room temperature for 15 min. The solvent was removedunder vacuum and the residue was diluted with water to give 63 mg (99%yield) ofN-[2-({4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperidinyl}sulfonyl)ethyl]-N,N-dimethylamine:¹H NMR (CDCl₃) δ 7.99 (d, J=7.9 Hz, 1H), 7.55 (t, J_(HF)=53.6 Hz, 1H),7.39 (t, J=8.3 Hz, 1H), 6.85 (d, J=7.9 Hz, 1H), 4.06 (s, 3H), 4.02-3.89(m, 6H), 3.85-3.78 (m, 4H), 3.14-3.11 (m, 2H), 2.97 (dt, J=12.2, 2.6 Hz,2H), 2.84-2.77 (m, 3H), 2.28 (s, 6H), 2.17 (br dd, J=13.2, 2.6 Hz, 2H),2.00 (ddd, J=25.1, 11.8, 4.1 Hz, 2H).

To a suspension ofN-[2-({4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperidinyl}sulfonyl)ethyl]-N,N-dimethylaminefrom the previous step in MeOH (50 mL) was added a slight excess of 1.25M HCl in MeOH (95 μL) to give a clear solution. The solvent was removedunder vacuum and the residue was washed with EtOAc to giveN-[2-({4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperidinyl}sulfonyl)ethyl]-N,N-dimethylaminehydrochloride: mp (MeOH/EtOAc) 243-245° C.; Anal. Calcd. forC₂₅H₃₅ClF₂N₈O₄S: C, 48.7; H, 5.7; N, 18.2; Cl, 5.7. Found: C, 48.7; H,5.7; N, 18.0; Cl, 5.7%.

Example 15 Synthesis of2-(difluoromethyl)-4-methoxy-1-[4-[1-(methylsulfonyl)-3-piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole

A mixture of1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole(0.40 g, 1 mmol), tert-butyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydropyridine-1(2H)-carboxylate(0.382 g, 1.24 mmol), PdCl₂(dppf) (63 mg), and 2 M aqueous Na₂CO₃ (8 mL)in dioxane (40 mL) was refluxed under nitrogen for 2 hrs. The dioxanewas removed under vacuum and the residue was extracted into CH₂Cl₂.Chromatography on silica eluting with hexanes/EtOAc (8:2) gave 0.27 g(50% yield) of tert-butyl5-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3,4-dihydro-1(2H)-pyridinecarboxylate:¹H NMR (CDCl₃) δ 8.59 (s, 1H), 7.99 (d, J=8.4 Hz, 1H), 7.60 (t,J_(HF)=53.6 Hz, 1H), 7.34 (t, J=8.2 Hz, 1H), 6.81 (d, J=8.1 Hz, 1H),4.04 (s, 3H), 4.02-3.75 (m, 8H), 3.71-3.64 (m, 2H), 2.56 (t, J=6.1 Hz,2H), 2.00-1.91 (m, 2H), 1.57 (s, 9H).

A solution of tert-butyl5-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3,4-dihydro-1(2H)-pyridinecarboxylate(272 mg, 0.50 mmol) in MeOH (20 mL) and THF (20 mL) was hydrogenatedover 10% Pd on carbon (50 mg). After removal of the hydrogen, themixture was refluxed in air for additional 2 hrs. The catalyst Pd/C wasremoved by filtration through celite, and the solvents were removedunder vacuum. Recrystallization of the residue from methanol gave 0.23 g(81% yield) of tert-butyl3-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperidinecarboxylate:mp 200-202° C.; ¹H NMR (CDCl₃) δ 8.01 (dd, J=8.4, 0.6 Hz, 1H), 7.58 (t,J_(HF)=53.6 Hz, 1H), 7.38 (t, J=8.2 Hz, 1H), 6.84 (d, J=8.1 Hz, 1H),4.47-4.35 (m, 1H), 4.06 (s, 3H), 3.96 (m, 4H), 3.85-3.77 (m, 4H), 3.09(dd, J=13.1, 10.7 Hz, 1H), 2.89-2.76 (m, 2H), 2.30-2.20 (m, 1H),1.88-1.57 (m, 4H), 1.48 (s, 9H); Anal. Calcd. for C₂₆H₃₃F₂N₇O₄: C, 57.2;H, 6.1; N, 18.0. Found: C, 57.1; H, 6.3; N, 17.8%.

Reaction of tert-butyl3-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperidinecarboxylate(0.22 g, 0.40 mmol) with TFA (0.5 mL) in CH₂Cl₂ (8 mL) gave2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(3-piperidinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole,which was dissolved in a mixture of CH₂Cl₂ (4 mL) and NEt₃ (0.29 mL, 2.1mmol) and cooled to 0° C. Methane sulfonyl chloride (0.05 mL, 0.65 mmol)was added, and the resulting mixture was allowed to warm to roomtemperature over 2 hrs. The reaction mixture was then diluted withwater, extracted with CH₂Cl₂, and dried. Chromatography on silicaeluting first with hexanes/EtOAc (4:1), followed by hexanes/EtOAc (1:1),and then CH₂Cl₂/MeOH (99:1), gave 0.19 g (91% yield) of2-(difluoromethyl)-4-methoxy-1-[4-[1-(methylsulfonyl)-3-piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole:mp 237-239° C.; ¹H NMR (CDCl₃) δ 7.98 (dd, J=8.4, 0.7 Hz, 1H), 7.54 (t,J_(HF)=53.5 Hz, 1H), 7.40 (t, J=8.3 Hz, 1H), 6.85 (d, J=8.1 Hz, 1H),4.08-3.92 (m, 8H), 3.86-3.72 (m, 5H), 3.14 (dd, J=11.5, 10.2 Hz, 1H),3.07-2.99 (m, 1H), 2.86-2.77 (m, 4H), 2.30-2.22 (m, 1H), 2.00-1.71 (m,3H); Anal. Calcd. for C₂₂H₂₇F₂N₇O₄S.0.5 H₂O: C, 49.6; H, 5.3; N, 18.4.Found: C, 49.7; H, 5.2; N, 18.3%.

Example 16 Synthesis of2-(difluoromethyl)-4-methoxy-1-[4-{[1-(methylsulfonyl)-4-piperidinyl]oxy}-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole

A mixture of 2,4-dichloro-6-(4-morpholinyl)-1,3,5-triazine (0.47 g, 2mmol), tert-butyl 4-hydroxy-1-piperidinecarboxylate (0.40 g, 2 mmol),and a small excess of NaH (58 mg, 2.4 mmol) in THF (20 mL) was stirredat room temperature overnight. The reaction was quenched with water, andthe mixture was extracted with EtOAc. Chromatography on silica elutingwith CH₂Cl₂/EtOAc (9:1) gave 0.65 g (81% yield) of tert-butyl4-(4-chloro-6-morpholino-1,3,5-triazin-2-yloxy)piperidine-1-carboxylateas a white solid: mp (i-Pr₂O) 150-152° C.; ¹H NMR (CDCl₃) ε 5.18 (tt,J=7.7, 3.8 Hz, 1H), 3.87 (m, 2H), 3.83 (m, 2H), 3.78-3.71 (m, 6H), 3.30(ddd, J=13.5, 8.3, 3.8 Hz, 2H), 1.95 (m, 2H), 1.78 (m, 2H), 1.46 (s,9H); Anal. Calcd. for C₁₇H₂₆ClN₅O₄: C, 51.06; H, 6.55; N, 17.51. Found:C, 51.21; H, 6.28; N, 17.4%.

A mixture of4-(4-chloro-6-morpholino-1,3,5-triazin-2-yloxy)piperidine-1-carboxylate(175 mg, 0.44 mmol), 2-(difluoromethyl)-4-methoxy-1H-benzimidazole (100mg, 0.505 mmol), and powdered K₂CO₃ (0.28 g, 2 mmol) in DMSO (10 mL) wasstirred at room temperature for 3 days, and then diluted with water. Theresulting precipitate was collected, washed with water, and dried.Chromatography on silica eluting with CH₂Cl₂/EtOAc (4:1) gave 200 mg(81% yield) of tert-butyl4-(4-(2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yloxy)piperidine-1-carboxylate:mp (CH₂Cl₂-MeOH) 191-193° C.; ¹H NMR (CDCl₃) δ 7.96 (dd, J=8.4, 0.5 Hz,1H), 7.49 (t, J_(HF)=53.5 Hz, 1H), 7.38 (t, J=8.3 Hz, 1H), 6.85 (d,J=7.8 Hz, 1H), 5.25 (m, 1H), 4.06 (s, 3H), 3.96-3.78 (m, 10H), 3.28 (m,2H), 2.50 (m, 2H), 1.85 (m, 2H), 1.48 (s, 9H); Anal. Calcd. forC₂₆H₃₃F₂N₇O₅: C, 55.61; H, 5.92; N, 17.46. Found: C, 55.77; H, 5.92; N,17.40%.

Treatment of tert-butyl4-(4-(2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yloxy)piperidine-1-carboxylate(112 mg, 0.2 mmol) with TFA (5 mL) in CH₂Cl₂ (10 mL), followed byquenching with aqueous NH₃ gave2-(difluoromethyl)-4-methoxy-1-(4-morpholinyl)-6-(4-piperidinyloxy)-1,3,5-triazin-2-yl]-1H-benzimidazole:¹H NMR (DMSO-d₆) δ 7.96 (dd, J=8.4, 0.5 Hz, 1H), 7.71 (t, J_(HF)=52.8Hz, 1H), 7.44 (t, J=8.3 Hz, 1H), 6.98 (d, J=7.7 Hz, 1H), 5.11 (m, 1H),3.98 (s, 3H), 3.83 (m, 4H), 3.71 (m, 4H), 3.00 (m, 2H), 2.62 (m, 2H),2.00 (m, 2H), 1.58 (m, 2H).

Reaction of2-(difluoromethyl)-4-methoxy-1-(4-morpholinyl)-6-(4-piperidinyloxy)-1,3,5-triazin-2-yl]-1H-benzimidazole(245 mg, 0.53 mmol) with methanesulfonyl chloride (0.5 mL, 6.87 mmol)and K₂CO₃ (2.0 g, 14.5 mmol) in CH₂Cl₂ (10 mL) gave2-(difluoromethyl)-4-methoxyl-[4-{[1-(methylsulfonyl)-4-piperidinyl]oxy}-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazolein 87% yield: mp (CH₂Cl₂/MeOH) 285-288° C.; ¹H NMR (DMSO-d₆) δ 7.96 (d,J=8.0 Hz, 1H), 7.71 (t, J_(HF)=52.9 Hz, 1H), 7.45 (t, J=8.2 Hz, 1H),6.99 (d, J=7.9 Hz, 1H), 5.27-5.21 (m, 1H), 3.98 (s, 3H), 3.84 (br m,4H), 3.75-3.71 (m, 4H), 3.46-3.38 (m, 2H), 3.20-3.14 (m, 2H), 2.93 (s,3H), 2.15-2.09 (m, 2H), 1.91-1.82 (m, 2H); Anal. Calcd. forC₂₂H₂₇F₂N₇O₅S: C, 49.0; H, 5.0; N, 18.2. Found: C, 49.0; H, 5.2; N,18.3%.

Example 17 Synthesis ofN-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}methanesulfonamide

A mixture of1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole(0.992 g, 2.5 mmol), tert-butyl 4-piperidinylcarbamate (1.00 g, 5 mmol),and DIPEA (0.65 g, 5 mmol) in THF (100 mL) was stirred at roomtemperature for 30 min. The solution was then concentrated and dilutedwith water (100 mL) containing 1 mL of acetic acid. The resulting solidwas collected, washed with water, and dried to give 1.38 g (98%) oftert-butyl1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinylcarbamate:mp (MeOH) 208-209° C.; ¹H NMR (CDCl₃) δ 7.88 (d, J=8.1 Hz, 1H), 7.48 (t,J_(HF)=53.6 Hz, 1H), 7.34 (t, J=8.2 Hz, 1H), 6.81 (d, J=7.9 Hz, 1H),4.66 (br d, J=13.4 Hz, 2H), 4.46 (m, exchangeable with D₂O, 1H), 4.04(s, 3H), 3.87 (m, 4H), 3.78 (m, 5H), 3.12 (m, 2H), 2.07 (br d, J=14.0Hz, 2H), 1.46 (s, 9H), 1.45-1.33 (m, 2H); Anal. Calcd. for C₂₆H₃₄F₂N₈O₄:C, 55.7; H, 6.1; N, 20.0. Found: C, 55.85; H, 6.1; N, 20.1%.

Treatment of tert-butyl1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinylcarbamate(0.28 g, 0.5 mmol) with TFA (5 mL) in CH₂Cl₂ (10 mL) gave1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinaminein a quantitative yield: ¹H NMR (CDCl₃) δ 7.90 (d, J=8.4 Hz, 1H), 7.51(t, J_(HF)=53.6 Hz, 1H), 7.34 (t, J=8.2 Hz, 1H), 6.81 (d, J=8.0 Hz, 1H),4.66 (br d, J=13.1 Hz, 2H), 4.05 (s, 3H), 3.88 (m, 4H), 3.78 (m, 4H),3.15-2.96 (m, 3H), 1.94 (m, 2H), 1.39-1.25 (m, 2H).

Reaction of1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinamine(460 mg, 1.0 mmol) with methanesulfonyl chloride (1 mL, 12.7 mmol) andK₂CO₃ (2.0 g, 14.5 mmol) in CH₂Cl₂ (10 mL) gaveN-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}methanesulfonamidein 97% yield: mp (CH₂Cl₂/MeOH) 225-228° C.; ¹H NMR (DMSO-d₆) δ 7.88 (d,J=8.0 Hz, 1H), 7.68 (t, J_(HF)=52.9 Hz, 1H), 7.41 (t, J=8.2 Hz, 1H),7.15 (d, J=5.7 Hz, 1H), 6.95 (d, J=7.8 Hz, 1H), 4.52-4.45 (m, 2H), 3.97(s, 3H), 3.81-3.79 (m, 4H), 3.70-3.69 (m, 4H), 3.50 (br m, 1H),3.29-3.21 (m, 2H), 2.96 (s, 3H), 1.96 (br, 2H), 1.44-1.42 (m, 2H); Anal.Calcd. for C₂₂H₂₈F₂N₈O₅S: C, 49.1; H, 5.2; N, 20.8. Found: C, 49.2; H,5.2; N, 20.9%.

Example 18 Synthesis ofN-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}-N-methylmethanesulfonamide

Reaction ofN-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}methanesulfonamide(Example 17) (114 mg, 0.21 mmol) with iodomethane (0.5 mL, 8.1 mmol) andK₂CO₃ (2 g, 14.5 mmol) in DMF (5 mL) gaveN-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}-N-methylmethanesulfonamide(98 mg) in 84% yield: mp (CH₂Cl₂/MeOH) 231-233° C.; ¹H NMR (DMSO-d₆) δ7.89 (d, J=8.2 Hz, 1H), 7.69 (t, J_(HF)=52.9 Hz, 1H), 7.41 (t, J=8.2 Hz,1H), 6.95 (d, J=7.9 Hz, 1H), 4.82-4.72 (m, 2H), 3.98 (s, 3H), 3.98-3.90(m, 2H), 3.82-3.79 (m, 4H), 3.70-3.69 (m, 4H), 3.11-2.98 (m, 2H), 2.94(s, 3H), 2.68 (s, 3H), 1.77-1.70 (m, 4H); Anal. Calcd. forC₂₃H₃₀F₂N₈O₄S: C, 50.0; H, 5.5; N, 20.3. Found: C, 49.9; H, 5.6; N,20.3%.

Example 19 Synthesis ofN¹-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N³—N³-dimethyl-N¹-[1-methylsulfonyl)-3-piperidinyl]-1,3-propanediamine

A mixture of tert-butyl 3-oxo-1-piperidinecarboxylate (5.0 g, 25.1 mmol)and 3-amino-1-propanol (5.66 mL, 73.8 mmol) in MeOH (75 mL) washydrogenated over 10% Pd on C (200 mg) for 1 day (Yokoyama et al.,Bioorg. Med. Chem. 2008, 16, 7968) to give tert-butyl3-[(3-hydroxypropyl)amino]-1-piperidinecarboxylate as an oil: ¹H NMR(CDCl₃) (rotamers) δ 3.80 (t, J=5.1 Hz, 2H), 3.80 (br, 1H), 3.65 and3.67 (2t, J=4.7 Hz, 1H), 3.06-2.86 (m, 4H), 2.62-2.56 (m, 1H), 1.90-1.86(m, 1H), 1.72-1.62 (m, 3H), 1.50-1.30 (m, 2H), 1.46 (s, 9H).

A mixture of tert-butyl3-[(3-hydroxypropyl)amino]-1-piperidinecarboxylate (516 mg, 2.00 mmol),1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole(610 mg, 1.54 mmol), and DIPEA (1.5 mL, excess) in DMF (20 mL) wasstirred at room temperature for 2 days. The reaction mixture was dilutedwith water and extracted with CH₂Cl₂ (3×30 mL). The combined extractswere washed with water, dried over Na₂SO₄, and concentrated.Chromatography of the residue on SiO₂ eluting with a gradient ofCH₂Cl₂/EtOAc (0-40%) gave tert-butyl3-[[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl](3-hydroxypropyl)-amino]-1-piperidinecarboxylate(854 mg, 90%): mp (CH₂Cl₂/hexanes) 109-191° C.; ¹H NMR (DMSO-d₆)(rotamers) δ 8.00 and 7.88 (2d, J=8.3, 8.4 Hz, 1H), 7.79 and 7.63 (2t,J_(HF)=53.0 Hz, 1H), 7.40-7.33 (m, 1H), 6.94 (dd, J=8.0, 4.13 Hz, 1H),4.60-4.48 and 4.29 (m, 2H), 3.98 and 3.97 (2s, 3H), 3.97-3.48 (m, 16H),2.93-2.88 and 2.66-2.64 (2m, 2H), 1.99-1.69 (m, 3H), 1.52-1.17 (m, 10H);Anal. Calcd. for C₂₉H₄₀F₂N₈O₅: C, 56.3; H, 6.5; N, 18.1. Found: C, 56.4;H, 6.4; N, 18.1%.

To a solution of tert-butyl3-[[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl](3-hydroxypropyl)-amino]-1-piperidinecarboxylate(420 mg, 0.72 mmol) in CH₂Cl₂ (12 mL) at 0° C. was added Et₃N (0.2 mL,1.4 mmol) and methanesulfonyl chloride (0.1 mL, 1.08 mmol). The reactionmixture was stirred at 0° C. for 30 min, and a solution of 40% aqueousdimethylamine (5 mL) was then added. The reaction mixture was stirred atroom temperature for 2 days and the solvent was removed under vacuum.The residue was diluted with water and stirred for 30 min to give aprecipitate, which was collected by filtration, washed with water, anddried. Chromatography on SiO₂ eluting first with CH₂Cl₂/EtOAc (4:1), andthen with CH₂Cl₂/MeOH (95:5) containing 1% aqueous NH₃, gave tert-butyl3-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl][3-(dimethylamino)propyl]amino}-1-piperidinecarboxylate(465 mg; 100%) as a white solid: mp (CH₂Cl₂/MeOH) 133-136° C.; ¹H NMR(DMSO-d₆) (rotamers) δ 7.96 and 7.88 (2d, J=8.3 Hz, 1H), 7.77 and 7.68(2t, J_(HF)=53.0, 52.9 Hz, 1H), 7.40-7.34 (m, 1H), 6.96-6.93 (m, 1H),4.56-4.88 and 4.30-4.27 (2 m, 1H), 3.98 and 3.97 (2s, 3H), 3.97-3.49 (m,13H), 2.93-2.88 and 2.77-2.63 (2m, 2H), 2.35-2.27 (m, 2H), 2.15 and 2.13(2s, 6H), 1.93-1.71 (m, 4H), 1.48-1.16 (m, 1H), 1.40 (s, 9H); Anal.Calcd. for C₃₁H₄₅F₂N₉O₄C, 57.7; H, 7.0; N, 19.5. Found: C, 57.7; H, 7.1;N, 19.7%.

To a solution of tert-butyl3-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl][3-(dimethylamino)propyl]amino}-1-piperidinecarboxylate(430 mg, 0.67 mmol) in CH₂Cl₂ (10 mL), was added TFA (5 mL). Theresulting mixture was stirred at room temperature for 30 min. Thesolvent and excess TFA were removed under vacuum. The residue wasdiluted with water and neutralized with aqueous NH₃. The resultingprecipitate was filtered, washed with water, and dried to giveN¹-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N³,N³-dimethyl-N¹-(3-piperidinyl)-1,3-propanediamine(323 mg, 88%): ¹H NMR (DMSO-d₆) (rotamers) δ 7.95 and 7.93 (2d, J=9.5,8.8 Hz, 1H), 7.77 and 7.71 (2t, J_(HF)=53.1 Hz, 1H), 7.42-7.36 (m, 1H),6.95 (d, J=1 Hz, 1H), 4.55-4.48 and 4.46-4.39 (2m, 1H), 3.98 (s, 3H),3.81-3.80 (m, 4H), 3.72-3.70 (m, 4H), 3.55-3.45 (m, 2H), 2.99-2.96 (m,1H), 2.92-2.89 (m, 1H), 2.77-2.66 (m, 1H), 2.45-2.40 (m, 1H), 2.27 (t,J=6.9 Hz, 2H), 2.16 and 2.12 (2s, 6H), 1.80-1.48 (m, 6H).

To a solution ofN¹-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N³,N³-dimethyl-N¹-(3-piperidinyl)-1,3-propanediamine(155 mg, 0.28 mmol) and DIPEA (1 mL) in CH₂Cl₂ (10 mL) was addedmethanesulfonyl chloride (0.5 mL) at 0° C. The resulting mixture wasstirred for 16 hrs at room temperature. After dilution with water, theorganic layer was separated, and the aqueous layer was further extractedwith CH₂Cl₂ (3×15 mL). The combined organic fractions were dried overNa₂SO₄, and the solvent removed under vacuum. The residue waschromatographed on alumina eluting with CH₂Cl₂/MeOH (97:3) to givepartially pure material, which was further purified by chromatography onsilica eluting with CH₂Cl₂/MeOH (97:3) to giveN¹-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N³,N³-dimethyl-N¹-[1-(methylsulfonyl)-3-piperidinyl]-1,3-propanediamine(125 mg, 72% yield).

To a suspension ofN¹-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N³,N³-dimethyl-N¹-[1-(methylsulfonyl)-3-piperidinyl]-1,3-propanediaminefrom the previous step in MeOH (20 mL) was added a slight excess of 1.25M HCl in MeOH (0.18 mL) to give a clear solution. The solvent wasremoved under vacuum and the residue was washed with EtOAc to giveN¹-[4-[2-(Difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N³,N³-dimethyl-N¹-[1-(methylsulfonyl)-3-piperidinyl]-1,3-propanediaminehydrochloride: mp (MeOH/EtOAc/hexanes) 189° C. (dec.); ¹H NMR (DMSO-d₆)(rotamers) δ 10.11 and 9.98 (2br, 1H), 7.89 (d, J=8.4 Hz, 1H), 7.71 and7.65 (2t, J_(HF)=52.8, 52.9 Hz, 1H), 7.45 and 7.38 (2t, J=8.2, 1H), 6.97and 6.95 (2d, J=5.7, 5.8 Hz, 1H), 4.73-4.65 and 4.51-4.44 (2m, 1H), 3.97and 3.96 (2s, 3H), 3.91-3.57 (m, 12H), 3.11-3.03 (m, 2H), 2.93 and 2.92(2s, 6H), 2.95-2.82 (m, 1H), 2.76-2.66 (m, 6H), 2.05-1.85 (m, 4H); Anal.Calcd. for C₂₇H₃₈N₉O₄.1.25HCl.0.5H₂O: C, 47.8; H, 6.1; Cl, 6.5; N, 18.6.Found: C, 47.6; H, 6.1; Cl, 6.6%; N, 17.8%.

Example 20 Synthesis of4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[1-(methylsulfonyl)-3-piperidinyl]-6-(4-morpholinyl)-N-[3-(4-morpholinyl)propyl]-1,3,5-triazin-2-amine

The title compound was made according to the procedure as described inExample 19.

Treatment of tert-butyl4-[[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl](3-hydroxypropyl)amino]-1-piperidinecarboxylatewith methanesulfonyl chloride and then morpholine gave tert-butyl3-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl][3-(4-morpholinyl)propyl]amino}-1-piperidinecarboxylateas a sticky oil; ¹H NMR (DMSO-d₆) (rotamers) δ 7.94 and 7.88 (2d, J=8.3,8.5 Hz, 1H), 7.62 and 7.73 (2t, J_(HF)=52.9, 53.5 Hz, 1H) 7.39 and 7.36(2t, J=8.2 Hz, 1H), 6.95 (t, J=8.0 Hz, 1H), 4.53 and 4.27 (2br, 1H),4.02-3.93 (m, 2H), 3.98 and 3.98 (2s, 3H), 3.80 and 3.70 (2br, 8H),3.55-3.53 (m, 4H), 2.94-2.62 (br m, 2H), 2.62-2.55 (m, 3H), 2.41-2.34(m, 5H), 1.94-1.72 (m, 5H), 1.47-1.40 (m, 1H), 1.40 (s, 9H).

Reaction of tert-butyl3-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl][3-(4-morpholinyl)propyl]amino}-1-piperidinecarboxylatewith TFA in CH₂Cl₂ gave4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-[3-(4-morpholinyl)propyl]-N-(3-piperidinyl)-1,3,5-triazin-2-amine,which was treated with methanesulfonyl chloride in CH₂Cl₂ to give4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[1-(methylsulfonyl)-3-piperidinyl]-6-(4-morpholinyl)-N-[3-(4-morpholinyl)propyl]-1,3,5-triazin-2-aminein 78% yield.

A suspension of4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[1-(methylsulfonyl)-3-piperidinyl]-6-(4-morpholinyl)-N-[3-(4-morpholinyl)propyl]-1,3,5-triazin-2-aminefrom the previous step in MeOH (20 mL) was treated with a slight excessof 1.25 M HCl in MeOH (1.1 equiv.) to give a clear solution. The solventwas removed under vacuum and the residue was washed with EtOAc to give4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[1-(methylsulfonyl)-3-piperidinyl]-6-(4-morpholinyl)-N-[3-(4-morpholinyl)propyl]-1,3,5-triazin-2-aminehydrochloride: mp (MeOH) 186-190° C.; ¹H NMR (DMSO-d₆) (rotamers) δ10.65 and 10.43 (2br, 1H), 7.90 and 7.89 (2d, J=8.2, 8.1, Hz, 1H), 7.70and 7.65 (2t, J_(HF)=52.9, Hz, 1H), 7.46 and 7.39 (2t, J=8.3, 8.2 Hz,1H), 6.96 (m, 1H), 4.75-4.66 and 4.51-4.44 (2m, 1H), 3.98 and 3.97 (2s,3H), 3.98-3.59 (m, 16H), 3.46-3.24 (m, 2H), 3.18-2.85 (m, 5H), 2.92 (s,3H), 2.73-2.67 (m, 1H), 2.09-1.89 (m, 6H); Anal. Calcd. forC₂₉H₄₂ClF₂N₉O₅S.1.25H₂O: C, 48.1; H, 6.2; N, 17.4; Cl, 4.9. Found: C,47.9; H, 6.2; N, 17.3; Cl, 5.2%.

Example 21 Synthesis ofN¹-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N³,N³-dimethyl-N¹-[1-(methylsulfonyl)-4-piperidinyl]-1,3-propanediamine

The title compound was made according to the procedure as described inExample 19.

Reaction of1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazolewith tert-butyl 4-[(3-hydroxypropyl)amino]-piperidine-1-carboxylate(Yokoyama et al., Bioorg. Med. Chem. 2008, 16, 7968) in DMF gavetert-butyl4-[[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl](3-hydroxypropyl)amino]-1-piperidinecarboxylate:¹H NMR (DMSO-d₆) (rotamers) δ 7.99 and 7.90 (2d, J=8.4, 8.5 Hz, 1H),7.78 and 7.70 (2t, J_(HF)=52.9, 52.3 Hz, 1H), 7.42 and 7.37 (2t, J=8.3Hz, 1H), 6.95 (d, J=8.0 Hz, 1H), 4.71-4.64 and 4.58-4.47 (2m, 2H),4.13-4.04 (m, 2H), 3.98 and 3.97 (2s, 3H), 3.79 and 3.69 (2br m, 8H),3.60-3.46 (m, 4H), 2.82-2.79 (m, 2H), 1.79-1.62 (m, 6H), 1.42 (br s,9H); Anal. Calcd. for C₂₄H₄₀F₂N₈O₅: C, 56.3; H, 6.5; N, 18.1. Found: C,56.4; H, 6.7; N, 18.0%.

Sequential treatment of tert-butyl4-[[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl](3-hydroxypropyl)amino]-1-piperidinecarboxylatewith methanesulfonyl chloride and aqueous 40% dimethylamine as inExample 19 gave tert-butyl4-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl][3-(dimethylamino)propyl]amino}-1-piperidine-carboxylatein 83% yield: ¹H NMR (DMSO-d₆) (rotamers) δ 7.96 and 7.90 (2d, J=8.3 Hz,1H), 7.77 and 7.70 (2t, J_(HF)=53.1, 53.0 Hz, 1H), 7.42 and 7.38 (t,J=8.3, 8.2 Hz, 1H), 6.95 (d, J=8.2 Hz, 1H), 4.71-4.64 and 4.55-4.45 (2m,1H), 4.13-4.02 (m, 2H), 3.98 (s, 3H), 3.81-3.77 (m, 4H), 3.66 (br, 4H),3.54-3.44 (m, 2H), 2.82 (br, 2H), 2.27 (t, J=6.8 Hz, 2H), 2.14 and 2.12(2s, 6H), 1.73-1.62 (m, 6H), 1.42 (s, 9H).

Reaction of tert-butyl4-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl][3-(dimethylamino)propyl]amino}-1-piperidine-carboxylatefrom the last step with TFA in CH₂Cl₂ gaveN¹-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N³,N³-dimethyl-N¹-(4-piperidinyl)-1,3-propanediaminein 99% yield: ¹H NMR (DMSO-d₆) (rotamers) δ 7.96 and 7.93 (d, J=8.3 Hz,1H), 7.77 and 7.70 (t, J_(HF)=53.1, 53.0 Hz, 1H), 7.40-7.35 (m, 1H),6.95 (d, J=8.1 Hz, 1H), 4.63-4.56 and 4.50-4.43 (2m, 1H), 3.98 (s, 3H),3.82-3.77 (m, 4H), 3.70 (br, 4H), 3.55-3.45 (m, 2H), 3.08-3.05 (m, 2H),2.59-2.52 (m, 3H), 2.28 (t, J=6.8 Hz, 2H), 2.14 and 2.12 (2s, 6H),1.76-1.61 (m, 6H).

Reaction ofN¹-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N³,N³-dimethyl-N¹-(4-piperidinyl)-1,3-propanediaminewith methanesulfonyl chloride gaveN¹-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N³,N³-dimethyl-N¹-[1-(methylsulfonyl)-4-piperidinyl]-1,3-propanediaminein 99% yield.

A suspension ofN¹-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N³,N³-dimethyl-N¹-[1-(methylsulfonyl)-4-piperidinyl]-1,3-propanediaminefrom the previous step in MeOH (20 mL) was treated with a slight excessof 1.25 M HCl in MeOH (1.1 equiv.) to give a clear solution. The solventwas removed under vacuum and the residue was washed with EtOAc to giveN¹-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N³,N³-dimethyl-N¹-[1-(methylsulfonyl)-4-piperidinyl]-1,3-propanediaminehydrochloride: mp (CH₂Cl₂/MeOH) 241-243° C.; ¹H NMR (DMSO-d₆) (rotamers)δ 9.95 (br, 1H), 7.90 and 7.89 (2d, J=8.2, 8.3 Hz, 1H), 7.71 and 7.70(2t, J_(HF)=52.9, 53.0 Hz, 1H), 7.45 (t, J=8.2 Hz, 1H), 6.96 (d, J=8.1Hz, 1H), 4.69-4.55 (m, 1H), 3.98 (s, 3H), 3.82-3.70 (m, 10H), 3.60-3.52(m, 2H), 3.12-3.05 (m, 2H), 2.94 and 2.92 (2s, 3H), 2.90-2.79 (m, 2H),2.74 and 2.70 (2s, 6H), 2.02-1.80 (m, 6H); Anal Calcd. forC₂₇H₃₉F₂N₉O₄S.1.25HCl.0.5H₂O: C, 47.8; H, 6.1; Cl, 6.5; N, 18.6. Found:C, 47.9; H, 6.0; Cl, 6.4; N, 18.6%.

Example 22 Synthesis of4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-N-[3-(4-morpholinyl)propyl]-1,3,5-triazin-2-amine

The title compound was made according to the procedure as described inExample 21.

Sequential reaction of tert-butyl4-[[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl](3-hydroxypropyl)amino]-1-piperidinecarboxylatewith methanesulfonyl chloride and morpholine gave tert-butyl4-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl][3-(4-morpholinyl)propyl]amino}-1-piperidinecarboxylate:¹H NMR (DMSO-d₆) (rotamers) δ 7.94 and 7.90 (2d, J=8.3, 8.2 Hz, 1H),7.73 and 7.70 (2t, J_(HF)=53.0 Hz, 1H), 7.42 and 7.38 (2t, J=8.2 Hz,1H), 6.95 (dd, J=8.0, 2.7 Hz, 1H), 4.72-4.59 and 4.58-4.82 (2m, 1H),4.17-4.06 (m, 2H), 3.98 (s, 3H), 3.80-3.77 (m, 4H), 3.69 (br, 4H),3.59-3.45 (m, 6H), 2.82 (br, 2H), 2.35-2.33 (m, 6H), 1.80-1.64 (m, 6H),1.42 (s, 9H).

Reaction of tert-butyl4-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl][3-(4-morpholinyl)propyl]amino}-1-piperidinecarboxylatewith TFA in CH₂Cl₂ gave4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-[3-(4-morpholinyl)propyl]-N-(4-piperidinyl)-1,3,5-triazin-2-amine(75% yield over two steps): ¹H NMR (DMSO-d₆) (rotamers) δ 7.94 (t, J=7.6Hz, 1H), 7.73 and 7.70 (2t, J_(HF)=53.1, 53.0 Hz, 1H), 7.42-7.36 (m,1H), 6.95 (d, J=8.1 Hz, 1H), 4.63-4.55 and 4.50-4.42 (2m, 1H), 3.98 (s,3H), 3.80-3.77 (m, 4H), 3.70 (br, 4H), 3.59-3.47 (m, 6H), 3.08-3.03 (m,2H), 2.60-2.53 (m, 2H), 2.36-2.33 (m, 6H), 1.85-1.59 (m, 6H).

Reaction of4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-[3-(4-morpholinyl)propyl]-N-(4-piperidinyl)-1,3,5-triazin-2-aminewith methane sulfonyl chloride in CH₂Cl₂ gave4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-N-[3-(4-morpholinyl)propyl]-1,3,5-triazin-2-aminein 90% yield.

4-[2-(Difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-N-[3-(4-morpholinyl)propyl]-1,3,5-triazin-2-aminehydrochloride: mp (MeOH) 268-271° C., ¹H NMR (DMSO-d₆) (rotamers) δ10.82 and 10.48 (2br, 1H), 7.89 (d, J=8.2 Hz, 1H), 7.71 and 7.70 (2t,J_(HF)=52.9 Hz, 1H), 7.48-7.43 (m, 1H), 6.96 (dd, J=8.0, 2.3 Hz, 1H),4.69-4.55 (m, 1H), 3.98 (s, 3H), 3.98-3.54 (m, 16H), 3.41-3.33 (m, 2H),3.19-3.12 (m, 2H), 3.08-2.98 (m, 2H), 2.94 and 2.93 (2s, 3H), 2.89-2.80(m, 2H), 2.09-1.85 (m, 6H); Anal. Calcd. for C₂₉H₄₂ClF₂N₉O₅S.0.5H₂O: C,49.0; H, 6.1; Cl, 5.0; N, 17.7. Found: C, 48.5; H, 6.0; Cl, 5.1; N;17.5%.

Example 23 Synthesis of4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-{3-[4-(methylsulfonyl)-1-piperazinyl]propyl}-N-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine

The title compound was made according to the procedure as described inExample 22.

Sequential reaction of tert-butyl4-[[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl](3-hydroxypropyl)amino]-1-piperidinecarboxylatewith methanesulfonyl chloride and tert-butyl 1-piperazinecarboxylategave tert-butyl4-(3-{[1-(tert-butoxycarbonyl)-4-piperidinyl][4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}propyl)-1-piperazinecarboxylate,as an oil; ¹H NMR (DMSO-d₆) (rotamers) δ 7.94 and 7.90 (2d, J=8.4, 8.3Hz, 1H), 7.72 and 7.70 (2t, J_(HF)=53.1 53.0 Hz, 1H), 7.42 and 7.38 (2t,J=8.2 Hz, 1H) 6.95 (d, J=8.1 Hz, 1H), 4.75-4.64 and 4.58-4.50 (2m, 1H),4.14-4.05 (m, 2H), 3.98 and 3.96 (2s, 3H), 3.80-3.77 (m, 4H), 3.69 (brm, 4H), 3.55-3.45 (m, 2H), 2.55-2.50 (m, 4), 2.37-2.28 (m, 9H), 1.67(br, 5H), 1.42 (s, 9H), 1.39 (s, 9H).

Deprotection of tert-butyl4-(3-{[1-(tert-butoxycarbonyl)-4-piperidinyl][4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}propyl)-1-piperazinecarboxylatewith TFA in CH₂Cl₂ gave4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-[3-(1-piperazinyl)propyl]-N-(4-piperidinyl)-1,3,5-triazin-2-amine:¹H NMR (DMSO-d₆) (rotamers) δ 7.95-7.91 (m, 1H), 7.73 and 7.70 (t,J_(HF)=53.0 Hz, 1H), 7.42-7.36 (m, 1H), 6.95 (d, J=8.08 Hz, 1H),4.70-4.45 (m, 2H), 3.98 (s, 3H), 3.80-3.79 (m, 4H), 3.70 (br m, 4H),3.56-3.46 (m, 2), 3.13-3.10 (m, 2H), 2.77-2.56 (m, 4H), 2.38-2.29 (m,8H), 1.78-1.69 (m, 7H).

Reaction of4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-[3-(1-piperazinyl)propyl]-N-(4-piperidinyl)-1,3,5-triazin-2-aminewith methane sulfonyl chloride in CH₂Cl₂ gave4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-{3-[4-(methylsulfonyl)-1-piperazinyl]propyl}-N-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-aminein 36% yield; mp (CH₂Cl₂/MeOH) 246-250° C.; ¹H NMR (DMSO-d₆) (rotamers)δ 7.94 and 7.89 (2d, J=8.3 Hz, 1H), 7.73 and 7.70 (2t, J_(HF)=53.0, 52.9Hz, 1H), 7.44 and 7.40 (2t, J=8.4, 8.2 Hz, 1H), 6.97 (dd, J=8.0, 3.3 Hz,1H), 4.68-4.51 (m, 1H), 3.98 (s, 3H), 3.81-3.69 (m, 10H), 3.59-3.48 (m,2H), 3.12-3.10 (m, 2H), 3.06-3.02 (m, 2H), 2.94 and 2.92 (2s, 3H),2.90-2.78 (m, 2H), 2.87 and 2.83 (2s, 3H), 2.55-2.39 (m, 6H), 1.92-1.75(m, 6H); Anal. Calcd. for C₃₀H₄₄F₂N₁₀O₆S₂.0.25H₂O: C, 48.2; H, 6.0; N,18.7. Found: C, 48.1; H, 6.0; N, 18.7%.

Example 24 Synthesis of4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-{3-[4-(methylsulfonyl)-1-piperazinyl]propyl}-N-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine

The title compound was made according to the procedure as described inExample 21.

Reaction of1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole(WO 2006/095906) with tert-butyl4-[(3-hydroxypropyl)amino]-1-piperidinecarboxylate in DMF and DIPEA asin Example 21 gave tert-butyl4-[[4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl](3-hydroxypropyl)amino]-1-piperidinecarboxylatein 83% yield: mp (CH₂Cl₂/hexanes) 188-190° C.; ¹H NMR (DMSO-d₆)(rotamers) δ 8.45 and 8.35 (2d, J=7.9, 8.3 Hz, 1H), 7.83 and 7.75 (2t,J_(HF)=52.9 Hz, 1H), 7.85 (2d, J=8.0 Hz, 1H), 7.54-7.41 (m, 2H),4.72-4.65 and 4.56-4.51 (2m, 1H), 4.58 and 4.48 (2t, J=4.8, 5.0 Hz, 1H),4.15-4.07 (m, 2H), 3.83-3.78 (m, 4H), 3.70 (m, 4H), 3.62-3.47 (m, 4H),2.81 (m, 2H), 1.78-1.65 (m, 6H), 1.42 (s, 9H); Anal Calcd. forC₂₈H₃₈F₂N₈O₄: C, 57.1; H, 6.5; N, 19.0. Found: C, 57.4; H, 6.3; N,19.1%.

Reaction of the above alcohol with methanesulfonyl chloride and aqueousdimethylamine as in Example 21 gave tert-butyl4-{[4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl][3-(dimethylamino)propyl]amino}-1-piperidinecarboxylatein 95% yield: mp (CH₂Cl₂/hexanes) 190-191° C.; ¹H NMR (DMSO-d₆)(rotamers) δ 8.41 and 8.35 (2d, J=7.6, 8.2 Hz, 1H), 7.85 (d, J=9 Hz,1H), 7.81 and 7.74 (2t, J_(HF)=53.0, 52.9 Hz, 1H), 7.54-7.41 (m, 2H),4.72-4.63 and 4.56-4.48 (2m, 1H), 4.14-4.07 (m, 2H), 3.83-3.78 (m, 4H),3.70 (m, 4H), 3.56-3.45 (m, 2H), 2.82 (m, 2H), 2.29-2.25 (m, 2H), 2.14and 2.12 (2s, 6H), 1.80-1.64 (m, 6H), 1.42 (s, 9H); Anal. Calcd. forC₃₀H₄₃F₂N₉O₃: C, 58.5; H, 7.0; N, 20.5. Found: C, 58.35; H, 7.3; N,20.3%.

Reaction of the above carbamate with TFA in CH₂Cl₂ as in Example 19 gaveN¹-[4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N³,N³-dimethyl-N¹-(4-piperidinyl)-1,3-propanediaminein 90% yield: ¹H NMR (DMSO-d₆) (rotamers) δ 8.41 and 8.37 (2d, J=7.7,8.1 Hz, 1H), 7.85 (d, J=7.9 Hz, 1H), 7.81 and 7.74 (2t, J_(HF)=53.0,52.9 Hz, 1H), 7.51-7.41 (m, 2H), 4.64-4.56 and 4.51-4.44 (2m, 1H),3.83-3.78 (m, 4H), 3.71 (m, 4H), 3.56-3.46 (m, 2H), 3.09-3.04 (m, 2H),2.60-2.51 (m, 2H), 2.31-2.26 (m, 2H), 2.15 and 2.12 (2s, 6H), 1.75-1.62(m, 6H).

Reaction of the above amine with methanesulfonyl chloride as in Example21 gaveN¹-[4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N³,N³-dimethyl-N¹-[1-(methylsulfonyl)-4-piperidinyl]-1,3-propanediaminein 90% yield. Hydrochloride: ¹H NMR (DMSO-d₆) (rotamers) δ 10.17 and10.0 (2br, 1H), 8.36 and 8.34 (2d, J=7.0 and 7.9 Hz, 1H), 7.76 and 7.74(2t, J_(HF)=52.8 Hz, 1H), 7.86 (d, J=8.3 Hz, 1H), 7.57-7.53 (m, 1H),7.46-7.43 (m, 1H), 4.70-4.56 (m, 1H), 3.84-3.71 (m, 10H), 3.62-3.53 (m,2H), 3.13-3.06 (m, 2H), 2.94 and 2.93 (2s, 3H), 2.90-2.80 (m, 2H), 2.74and 2.70 (2s, 6H), 1.99-1.87 (m, 6H); Anal. Calcd. forC₂₆H₃₈ClF₂N₉O₃S.0.5H₂O: C, 48.9; H, 6.15; N, 19.7; Cl, 5.6. Found: C,48.9; H, 6.3; N, 19.8; Cl, 5.7%.

Example 25 Synthesis of4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine

tert-Butyl4-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}-1-piperidinecarboxylate(Example 5) was reacted with TFA in CH₂Cl₂ to give4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-(4-piperidinyl)-1,3,5-triazin-2-amine,which was reacted directly with methanesulfonyl chloride to give4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-aminein 83% yield: mp (CH₂Cl₂/MeOH) 270-272° C.; ¹H NMR (DMSO-d₆) δ8.11-7.59(m, 3H), 7.42 and 7.38 (2t, J=8.3. 8.4 Hz, 1H), 6.95 and 6.94 (2m,J=8.0, 7.8 Hz, 1H), 3.98 and 3.97 (2s, 3H), 3.79 (m, 4H), 3.70-3.69 (m,4H), 3.60-3.56 (m, 2H), 3.56-3.24 (m, 1H), 2.94-2.85 (m, 5H), 2.04-1.97(m, 2H), 1.65-1.54 (m, 2H); Anal. Calcd. for C₂₂H₂₈F₂N₈O₄S: C, 49.1; H,5.2; N, 20.8. Found: C, 49.3; H, 5.3; N, 20.9%.

Example 26 Synthesis of3-{4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-[4-(methylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-8-oxa-3-azabicyclo[3.2.1]octane

A mixture of 2-(difluoromethyl)-4-methoxy-1H-benzimidazole (0.99 g, 5mmol), tert-butyl4-(4,6-dichloro-1,3,5-triazin-2-yl)piperazine-1-carboxylate (Eur. J.Org. Chem. 2001, 2825-2839) (2.0 g, 6 mmol), and 3.5 g (25 mmol)powdered K₂CO₃ in 40 mL DMF was stirred at room temperature for 1 hr.Water was added and the product was collected by filtration and washedsuccessively with water and cold ethanol to give 2.14 g (86% yield) oftert-butyl4-{4-chloro-6-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-1,3,5-triazin-2-yl}-1-piperazinecarboxylate:mp (CH₂Cl₂/EtOH)>300° C.; ¹H NMR (CDCl₃) δ7.99 (d, J=8.3 Hz, 1H), 7.48(t, J_(HF)=53.4 Hz, 1H), 7.41 (t, J=8.3 Hz, 1H), 6.87 (d, J=8.0 Hz, 1H),4.06 (s, 3H), 3.95 (m, 4H), 3.58 (m, 4H), 1.50 (s, 9H); Anal. Calcd. forC₂₁H₂₄ClF₂N₇O₃: C, 50.9; H, 4.9; N, 19.8. Found: C, 51.1; H, 4.9; N,19.95%.

A mixture of tert-butyl4-{4-chloro-6-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-1,3,5-triazin-2-yl}-1-piperazinecarboxylate(550 mg, 1.11 mmol), 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (215mg, 1.44 mmol) and DIPEA (0.77 mL, 4.44 mmol) in THF (20 mL) was stirredat room temperature overnight. The solvent was removed under vacuum andthe residue diluted with water. The resulting precipitate was washedwith water, dissolved in CH₂Cl₂, dried (Na₂SO₄) and recrystallized fromCH₂Cl₂/MeOH to give 540 mg (85% yield) of tert-butyl4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]-1-piperazinecarboxylate:mp (CH₂Cl₂/MeOH) 181-183° C.; ¹H NMR (CDCl₃) δ7.89 (dd, J=8.4, 0.6 Hz,1H), 7.49 (t, J_(HF)=53.6 Hz, 1H), 7.35 (t, J=8.2 Hz, 1H), 6.81 (d,J=7.6, 1H), 4.48 (d, J=8.0 Hz, 2H), 4.33 (dd, J=12.6, 8.9 Hz, 2H), 4.05(s, 3H), 3.87 (br s, 4H), 3.53 (br s, 4H), 3.29 (ddd, J=32.8, 13.1, 1.6Hz, 2H), 1.99 (dd, J=8.3, 4.4 Hz, 2H), 1.79 (m, 2H), 1.50 (s, 9H); Anal.Calcd. for C₂₇H₃₄F₂N₈O₄.0.05H₂O: C, 56.55; H, 6.0; N, 19.5. Found: C,56.2; H, 6.0; N, 19.6.

Reaction of tert-butyl4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]-1-piperazinecarboxylate(513 mg, 0.896 mmol) with an excess of TFA (2 mL) in CH₂Cl₂ (10 mL) atroom temperature for 3 hrs, followed by treatment with aq. NH₃ gave 385mg (91% yield) of3-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(1-piperazinyl)-1,3,5-triazin-2-yl]-8-oxa-3-azabicyclo[3.2.1]octane:mp 221-223° C.; ¹H NMR (CDCl₃) δ7.90 (dd, J=8.4, 0.6 Hz, 1H), 7.51 (t,J_(HF)=53.6 Hz, 1H), 7.35 (t, J=8.2 Hz, 1H), 6.81 (d, J=7.7 Hz, 1H),4.47 (d, J=9.6 Hz, 2H), 4.33 (t, J=12.1 Hz, 2H), 4.05 (s, 3H), 3.86 (brs, 4H), 3.28 (dd, J=32.5, 12.3 Hz, 2H), 2.95 (br s, 4H), 1.98 (dd,J=8.3, 4.5 Hz, 2H), 1.80 (m, 2H).

Methanesulfonyl chloride (0.12 mL, 1.55 mmol) was added dropwise to astirred suspension of3-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(1-piperazinyl)-1,3,5-triazin-2-yl]-8-oxa-3-azabicyclo[3.2.1]octane(165 mg, 0.349 mmol) and powdered K₂CO₃ (434 mg, 3.15 mmol) in CH₂Cl₂ (5mL) at 0° C. The reaction mixture was allowed to warm to roomtemperature and was stirred for 3 days. Water was added, the phases wereseparated and the aqueous phase was extracted with CH₂Cl₂. The combinedorganic phases were dried (Na₂SO₄) and the solvent removed under vacuum.Chromatography on silica, eluting with CH₂Cl₂/MeOH (99:1), followed byrecrystallization from CH₂Cl₂/MeOH gave 170 mg (89% yield) of3-{4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-[4-(methylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-8-oxa-3-azabicyclo[3.2.1]octane:mp (CH₂Cl₂/MeOH) 312-314° C.; ¹H NMR (CDCl₃) δ7.86 (dd, J=8.4, 0.6 Hz,1H), 7.45 (t, J_(HF)=53.6 Hz, 1H), 7.36 (t, J=8.2 Hz, 1H), 6.82 (d,J=7.8 Hz, 1H), 4.49 (br s, 2H), 4.32 (d, J=13.2 Hz, 2H), 4.05 (s, 3H),4.02 (br s, 4H), 3.30 (m, 6H), 2.81 (s, 3H), 1.99 (m, 2H), 1.79 (m, 2H);Anal. Calcd. for C₂₃H₂₈F₂N₈O₄S: C, 50.2; H, 5.1; N, 20.35. Found: C,50.3; H, 5.1; N, 20.5.

Example 27 Synthesis of2-(difluoromethyl)-4-methoxy-1-[4-[4-(methylsulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-2-pyrimidinyl]-1H-benzimidazole

A solution of 0.223 g (0.5 mmol) of2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(1-piperazinyl)-2-pyrimidinyl]-1H-benzimidazole(WO 2008/032064) and 0.345 g (2.5 mmol) of powdered K₂CO₃ in 20 mLCH₂Cl₂ was cooled to 0° C., and 0.086 g (0.75 mmol) of methanesulfonylchloride was added. The reaction mixture was allowed to warm to roomtemperature, and after stirring overnight water was added. The organiclayer was separated, washed successively with aqueous acetic acid andaq. ammonia, and dried. Chromatography on silica, eluting withCH₂Cl₂/EtOAc (4:1) gave 0.176 g (67% yield) of2-(difluoromethyl)-4-methoxy-1-[4-[4-(methylsulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-2-pyrimidinyl]-1H-benzimidazole:mp (MeOH) 273-274° C.; ¹H NMR (CDCl₃) δ7.74 (dd, J=8.4, 0.6 Hz, 1H),7.38 (t, J_(HF)=53.5 Hz, 1H), 7.33 (t, J=8.2 Hz, 1H), 6.79 (t, J=7.6 Hz,1H), 5.54 (s, 1H), 4.05 (s, 3H), 3.83-3.79 (m, 8H), 3.64 (m, 4H), 3.35(m, 4H), 2.82 (s, 3H); Anal. Calcd. for C₂₂H₂₇F₂N₇O₄S: C, 50.5; H, 5.2;N, 18.7. Found: C, 50.7; H, 5.3; N, 18.75%.

Example 28 Synthesis of4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[1-(methylsulfonyl)-3-azetidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine

Reaction of1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazolewith tert-butyl 3-amino-1-azetidinecarboxylate gave tert-butyl3-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}-1-azetidinecarboxylatein 86% yield: mp (CH₂Cl₂/hexanes) 201-203° C.; ¹H NMR (DMSO-d₆)(rotamers) δ 8.50 and 8.45 (2d, J=6.3, 6.5 Hz, 1H), 8.01 and 7.93 (2d,J=8.2, 8.3 Hz, 1H), 7.83 and 7.44 (2t, J_(HF)=53.1, 52.9 Hz, 1H),7.44-7.37 (m, 1H), 6.96 and 6.95 (2d, J=8.1, 8.0 Hz, 1H), 4.73-4.58 (m,1H), 4.78 (t, J=7.8 Hz, 2H), 3.97 (s, 3H), 3.87-3.82 (m, 2H), 3.78 (m,4H), 3.69, (m, 4H), 1 40 and 1.39 (2s, 9H); Anal. Calcd. forC₂₄H₃₀F₂N₈O₄: C, 54.1; H, 5.7; N, 21.0. Found: C, 54.0; 5.8; N, 21.0%.

Deprotection of the above carbamate with TFA in CH₂Cl₂ gaveN-(3-azetidinyl)-4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-aminein 100% yield: ¹H NMR (DMSO-d₆) (rotamers) δ 8.58 and 8.54 (2d, J=5.9,6.6 Hz, 1H), 8.07 and 7.91 (2d, J=8.4, 8.3 Hz, 1H), 7.82 and 7.70 (2t,J_(HF)=51.3 and 52.9 Hz, 1H), 7.44-7.38 (m, 1H), 6.97 and 6.96 (2d,J=7.9, 8.0 Hz, 1H), 4.98-4.88 and 4.88-4.80 (2m, 1H), 4.23-4.16 (m, 2H),4.06-3.98 (m, 2H), 3.98 (s, 3H), 3.80-3.78 (m, 4H), 3.70 (m, 4H).

A mixture of the above amine (573 mg, 1.32 mmol) and dry powdered K₂CO₃(4.0 g, 29.0 mmol) in CH₂Cl₂ (30 mL) at 0° C. was treated withmethanesulfonyl chloride (0.5 mL, 6.5 mmol). The reaction mixture wasstirred at 20° C. for 20 hrs, diluted with water (100 mL), and theCH₂Cl₂ was separated and removed under vacuum. The residue was washedwith water and dried. Recrystallization from CH₂Cl₂/MeOH gave 550 mg(81% yield) of4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[1-(methylsulfonyl)-3-azetidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine:mp (CH₂Cl₂/MeOH) 240-242° C.; ¹H NMR (DMSO-d₆) δ 8.55 and 8.50 (2d,J=6.2 and 6.8 Hz, 1H), 8.09 and 7.93 (2d, J=8.3 and 8.4 Hz, 1H), 7.82and 7.72 (2t, J_(HF)=53.1 and 52.9 Hz, 1H), 7.44 and 7.39 (2t, J=8.3 and8.2 Hz, 1H), 6.96 and 6.95 (2d, J=8.00 Hz, 1H), 4.82-4.66 (m, 1H),4.19-4.12 (m, 2H), 3.97 (s, 3H), 3.94-3.88 (m, 2H), 3.79 (m, 4H), 3.69(m, 4H), 3.04 (s, 3H); Anal. Calcd. for C₂₀H₂₄F₂N₈O₄S: C, 47.1; H, 4.7;N, 22.0. Found: C, 47.0; H, 4.9; N, 21.7%.

Example 29 Synthesis of4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-methyl-N-[1-(methylsulfonyl)-3-azetidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine

To a solution of4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[1-(methylsulfonyl)-3-azetidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine(Example 28) (170 mg, 0.33 mmol) in DMF (4 mL) at 0° C. was added NaH(24 mg, 1.0 mmol). The mixture was stirred for 30 min at thistemperature and iodomethane (0.3 mL, excess) was added. The resultingmixture was allowed to warm to 20° C. and stirred for 2 hrs. Water wasadded and the resulting precipitate was filtered, washed with water, anddried. Recrystallization from CH₂Cl₂/MeOH gave4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-methyl-N-[1-(methylsulfonyl)-3-azetidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine(156 mg, 89% yield): mp (CH₂Cl₂/MeOH) 242-244° C.; ¹H NMR (DMSO-d₆)δ7.97-7.60 (m, 2H), 7.42 (t, J=8.1 Hz, 1H), 6.96 (d, J=7.9 Hz, 1H), 5.50and 5.26 (2m, 1H), 4.17-4.12 (m, 4H), 3.98 (s, 3H), 3.81 (m, 4H),3.71-3.69 (m, 4H), 3.24 (s, 3H), 3.09 (s, 3H); Anal. Calcd. forC₂₁H₂₆F₂N₈O₄S: C, 48.1; H, 5.0; N, 21.3. Found: C, 48.0; H, 5.0; N,21.3%.

Example 30 Synthesis ofN-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-azetidinyl}methanesulfonamide

Reaction of1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazoleand tert-butyl 3-azetidinylcarbamate gave tert-butyl1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-azetidinylcarbamatein 90% yield: mp (CH₂Cl₂/hexanes) 217-220° C.; ¹H NMR (DMSO-d₆) δ 7.98(d, J=8.0 Hz, 1H), 7.73 (t, J_(HF)=53.0 Hz, 1H), 8.24 (t, J=8.2 Hz, 1H),6.95 (d, J=7.8 Hz, 1H), 4.42 and 4.36-4.32 (2m, 3H), 4.01-3.98 (m, 2H),3.79-3.77 (m, 4H), 3.68 (m, 4H), 1.40 (s, 9H). Anal. Calcd. forC₂₄H₃₀F₂N₈O₄: C, 54.1; H, 5.7; N, 21.0. Found: C, 54.4; H, 5.8; N,21.2%.

Deprotection of the above carbamate with TFA in CH₂Cl₂ gave1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-azetidinaminein 100% yield: ¹H NMR (DMSO-d₆) δ 7.99 (d, J=8.4 Hz, 1H), 7.74 (t,J_(HF)=53.1 Hz, 1H), 7.40 (t, J=8.2 Hz, 1H), 6.94 (d, J=7.8 Hz, 1H),4.35-4.32 and 4.27-4.23 (2m, 2H), 3.97 (s, 3H), 3.87-3.68 (m, 10H), 2.21(br, exchangeable with D₂O, 2H).

Reaction of1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-azetidinamineand methanesulfonyl chloride as in Example 28 gaveN-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-azetidinyl}methanesulfonamidein 86% yield: mp 307-309° C.; ¹H NMR (DMSO-d₆) δ 7.98 (d, J=8.1 Hz, 1H),7.92 (br s, 1H), 7.73 (t, J_(HF)=53.0 Hz, 1H), 7.40 (t, J=8.2 Hz, 1H),6.95 (d, J=7.7 Hz, 1H), 4.54-4.33 (m, 3H), 4.07-3.97 (m, 2H), 3.97 (s,3H), 3.80-3.78 (m, 4H), 3.69 (m, 4H), 2.97 (s, 3H); Anal. Calcd. forC₂₀H₂₄F₂N₈O₄S.0.25H₂O: C, 46.6; H, 4.8; N, 21.8. Found: C, 46.7; H, 4.8;N, 22.0%.

Example 31 Synthesis ofN-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-azetidinyl}-N-methylmethanesulfonamide

To a solution of compoundN-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-azetidinyl}methanesulfonamide(Example 30) (182 mg, 0.36 mmol) in DMF (4 mL) was added dry powderedK₂CO₃ (1.0 g, 7.3 mmol) and iodomethane (0.5 mL, excess). The reactionmixture was stirred at 20° C. for 20 hrs and diluted with water. Theresulting precipitate was collected by filtration, washed with water,and dried. Recrystallization from CH₂Cl₂/MeOH gaveN-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-azetidinyl}-N-methylmethanesulfonamidein 83% yield: mp (CH₂Cl₂/MeOH) 290-291; ¹H NMR (DMSO-d₆) δ7.99 (d, J=7.8Hz, 1H), 7.75 (t, J_(HF)=53.0 Hz, 1H), 7.40 (t, J=8.2 Hz, 1H), 6.95 (d,J=7.7 Hz, 1H), 4.78-4.71 (m, 1H), 4.46-4.26 (m, 4H), 3.98 (s, 3H),3.80-3.79 (m, 4H), 3.69 (m, 4H), 2.93 (s, 3H), 2.91 (s, 3H); Anal.Calcd. for C₂₁H₂₆F₂N₈O₄S: C, 48.1; H, 5.0; N, 21.4. Found: C, 47.9; H,4.9; N, 21.5%.

Example 32 Synthesis of4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[(3R)-1-(methylsulfonyl)pyrrolidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine

A mixture of1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole(420 mg, 1.06 mmol), tert-butyl(3R)-pyrrolidinylcarbamate (0.24 g, 1.27mmol), and DIPEA (0.3 mL, 1.6 mmol) in THF (25 mL) was stirred at 20° C.for 20 hrs. The reaction mixture was diluted with water (100 mL), andthe resulting precipitate was filtered, washed with water, and dried.Recrystallization from CH₂Cl₂/hexanes gave 554 mg (96% yield) oftert-butyl(3R)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]pyrrolidinylcarbamate:mp 151-153° C.; ¹H NMR (DMSO-d₆) δ8.01 and 7.98 (2d, J=8.3, 8.9 Hz, 1H),7.77 and 7.74 (2t, J_(HF)=53.0 Hz, 1H) 7.40 and 7.39 (2t, J=8.2 Hz, 1H),7.20 (br s, exchangeable with D₂O, 1H), 6.94 (d, J=8.1 Hz, 1H), 4.13(br, 1H), 3.92 (s, 3H), 3.79 (m, 4H), 3.78-3.37 (m, 2H), 3.68 (m, 4H),3.28 (m, 2H), 2.20-2.08 and 1.95-1.84 (2m, 2H), 1.40 (s, 9H).

A solution oftert-butyl(3R)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]pyrrolidinylcarbamate(200 mg, 0.36 mmol) in CH₂Cl₂ (10 mL) was treated with TFA (5 mL) andstirred for 3 hrs. The solvent and excess TFA were removed under vacuum,and the resulting residue was diluted with H₂O (50 mL), and basifiedwith aq. NH₃. The resulting precipitate was filtered, washed with water,and dried to give 143 mg (89% yield) of(3R)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-pyrrolidinamine.

Reaction of4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-[(3R)-pyrrolidinyl]-1,3,5-triazin-2-amineand methanesulfonyl chloride as in Example 28 gave4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[(3R)-1-(methylsulfonyl)pyrrolidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-aminein 44% yield: mp (CH₂Cl₂/MeOH) 260-261° C.; ¹H NMR (DMSO-d₆) δ8.19 and8.13 (2d, J=6.3, 6.7 Hz, 1H), 8.10 and 7.96 (2d, J=8.3, 8.4 Hz, 1H),7.86 and 7.73 (2t, J_(HF)=53.0, 52.9 Hz, 1H), 7.43-7.36 (m, 1H), 6.96and 6.94 (2d, J=8.0 Hz, 1H), 4.61-4.48 9 (m, 1H), 3.97 (s, 3H), 3.79 (m,4H), 3.70 (m, 4H), 3.61-3.57 and 3.50-3.44 (2m, 2H), 3.38-3.32 and3.24-3.21 (2m, 2H), 2.924 and 2.918 (2s, 3H), 2.29-2.19 and 2.04-1.96(2m, 2H); Anal. Calcd. for C₂₁H₂₆F₂N₈O₄S: C, 48.1; H, 5.0; N, 21.4.Found: C, 48.3; H, 5.2; N, 21.5%.

Example 33 Synthesis of4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-methyl-N-[(3R)-1-(methylsulfonyl)pyrrolidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine

Methylation of4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[(3R)-1-(methylsulfonyl)pyrrolidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine(Example 33) with NaH and iodomethane in DMF as in Example 29 gave4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-methyl-N-[(3R)-1-(methylsulfonyl)pyrrolidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-aminein 87% yield: mp (CH₂Cl₂/MeOH) 238-240° C.; ¹H NMR (DMSO-d₆) δ7.95-7.95(m, 2H), 7.40 (t, J=8.2 Hz, 1H), 6.95 (d, J=7.8 Hz, 1H), 5.42-5.35 (m,1H), 3.98 (s, 3H), 3.82 (m, 4H), 3.71-3.70 (m, 4H), 3.55-3.44 (m, 2H),3.35-3.25 (m, 2H), 3.14 (br s, 3H), 2.97 (s, 3H), 2.21-2.09 (m, 2H);Anal. Calcd. for C₂₂H₂₈F₂N₈O₄S: C, 49.1; H, 5.2; N, 20.8. Found: C,49.3; H, 5.2; 21.0%.

Example 34 Synthesis of4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[(3S)-1-(methylsulfonyl)pyrrolidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine

Reaction of1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazolewith tert-butyl(3S)-pyrrolidinylcarbamate as in Example 32 gavetert-butyl(3S)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]pyrrolidinylcarbamatein 91% yield as a white solid: mp (CH₂Cl₂/MeOH) 292° C. dec.; ¹H NMR(DMSO-d₆) δ8.01 and 7.98 (2d, J=8.2, 8.4 Hz, 1H), 7.77 and 7.75 (2t,J_(HF)=53.0 Hz, 1H), 7.40 (2t, J=8.2 Hz, 1H), 7.21 (br, exchangeablewith D₂O, 1H), 6.95 (d, J=8.0 Hz, 1H), 4.15-411 (m, 1H), 3.97 (s, 3H),3.79-3.37 (m, 12H), 3.00-2.08 and 1.95-1.05 (2m, 2H), 1.40 (s, 9H).

Deprotection of the carbamate with TFA in CH₂Cl₂ gave(3S)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-pyrrolidinaminein 95% yield.

Reaction of4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-[(3S)-pyrrolidinyl]-1,3,5-triazin-2-amineand methanesulfonyl chloride as in Example 28 gave4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[(3S)-1-(methylsulfonyl)pyrrolidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-aminein 42% yield: mp (CH₂Cl₂/MeOH) 260-261° C.; ¹H NMR (DMSO-d₆) δ8.19 and8.13 (2d, J=6.4, 6.8 Hz, 1H), 8.10 and 7.96 (2d, J=8.3, 8.4 Hz, 1H),7.86 and 7.73 (2t, J_(HF)=53.1, 52.9 Hz, 1H), 7.43-7.36 (m, 1H), 6.96and 6.94 (2d, J=8.0, 7.9 Hz, 1H), 4.59-4.48 (m, 1H), 3.97 (s, 3H), 3.79(m, 4H), 3.70 (m, 4H), 3.61-3.57 and 3.50-3.44 (2m, 2H), 3.39-3.32 and3.24-3.21 (2 m, 2H), 2.923 and 2.917 (2s, 3H), 2.29-2.19 and 2.04-1.96(2m, 2H); Anal. Calcd. for C₂₁H₂₆F₂N₈O₄S: C, 48.1; H, 5.0; N, 21.4.Found: C, 48.2; H, 5.0; N, 21.5%.

Example 35 Synthesis of4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-methyl-N-[(3S)-1-(methylsulfonyl)pyrrolidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine

Methylation of4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[(3S)-1-(methylsulfonyl)pyrrolidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine(Example 34) with iodomethane in the presence of NaH in DMF as inExample 29 gave4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-methyl-N-[(3S)-1-(methylsulfonyl)pyrrolidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-aminein 90% yield: mp (CH₂Cl₂/MeOH) 238-240° C.; ¹H NMR (DMSO-d₆) δ7.97-7.59(m, 2H), 7.41 (t, J=8.2 Hz, 1H), 6.9 (d, J=7.8 Hz, 1H), 5.42-5.35 (m,1H), 3.98 (s, 3H), 3.82 (m, 4H), 3.71-3.70 (m, 4H), 3.54-3.44 (m, 2H),3.35-3.24 (m, 2H), 3.14 (br s, 3H), 2.97 (s, 3H), 2.21-2.09 (m, 2H);Anal. Calcd. for C₂₂H₂₈F₂N₈O₄S: C, 49.1; H, 5.2; N, 20.8. Found: C,49.3; H, 5.2; 21.0%.

Example 36 Synthesis ofN-{(3R)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]pyrrolidinyl}methanesulfonamide

A mixture of1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole(420 mg, 1.06 mmol), tert-butyl(3R)-pyrrolidinylcarbamate (0.24 g, 1.27mmol), and DIPEA (0.3 mL, 1.6 mmol) in THF (25 mL) was stirred at 20° C.for 20 hrs. The reaction mixture was diluted with water (100 mL), andthe resulting precipitate was filtered, washed with water, andrecrystallized from CH₂Cl₂/hexanes to give 554 mg (96% yield) oftert-butyl(3R)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]pyrrolidinylcarbamate:mp 151-153° C.; ¹H NMR (DMSO-d₆) δ8.01 and 7.98 (2d, J=8.3, 8.9 Hz, 1H),7.77 and 7.74 (2t, J_(HF)=53.0 Hz, 1H) 7.40 and 7.39 (2t, J=8.2 Hz, 1H),7.20 (br s, exchangeable with D₂O, 1H), 6.94 (d, J=8.1 Hz, 1H), 4.13(br, 1H), 3.92 (s, 3H), 3.79 (m, 4H), 3.78-3.37 (m, 2H), 3.68 (m, 4H),3.28 (m, 2H), 2.20-2.08 and 1.95-1.84 (2m, 2H), 1.40 (s, 9H).

A solution oftert-butyl(3R)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]pyrrolidinylcarbamate(200 mg, 0.36 mmol) in CH₂Cl₂ (10 mL) was treated with TFA (5 mL) andstirred for 3 hrs. The solvent and excess TFA was evaporated at 20° C.under vacuum, and the resulting residue was diluted with H₂O (50 mL),and basified with aq. NH₃. The resulting precipitate was filtered,washed with water and dried to give 143 mg (89% yield) of(3R)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-pyrrolidinamine.

Reaction of(3R)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-pyrrolidinaminewith methanesulfonyl chloride as in Example 28 gaveN-{(3R)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]pyrrolidinyl}methanesulfonamidein 90% yield: mp (CH₂Cl₂/MeOH) 290-292° C.; ¹H NMR (DMSO-d₆) δ8.00 (t,J=8.7 Hz, 1H), 7.77 and 7.75 (2t, J_(HF)=53.0 Hz, 1H), 7.43 (br s, 1H),7.40 (dt, J=8.3, 2.5 Hz, 1H), 6.95 (d, J=8.0 Hz, 1H), 4.11-4.02 (m, 1H),3.98 (s, 3H), 3.90-3.45 (m, 12H), 3.00 and 2.59 (2s, 3H), 2.30-2.19 and(2m, 2H); Anal. Calcd. for C₂₁H₂₆F₂N₈O₄S: C, 48.1; H, 5.0; N, 21.4.Found: C, 48.2; H, 5.1; N, 21.6%.

Example 37 Synthesis ofN-{(3R)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]pyrrolidinyl}-N-methylmethanesulfonamide

Methylation ofN-{(3R)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]pyrrolidinyl}methanesulfonamide(Example 36) with iodomethane in the presence of K₂CO₃ in DMF as inExample 31 gaveN-{(3R)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]pyrrolidinyl}-N-methylmethanesulfonamidein 94% yield: mp (CH₂Cl₂/MeOH) 242-244° C.; ¹H NMR (DMSO-d₆) δ8.01 (d,J=8.10 Hz, 1H), 7.78 and 7.77 (2t, J_(HF)=53.0, Hz, 1H), 7.41 (dt,J=8.3, 2.2 Hz, 1H), 6.95 (d, J=8.0 Hz, 1H), 4.57-4.46 (m, 1H)′ 3.98 (s,3H), 3.92-3.82 (m, 6H), 3.70-3.69 (m, 4H), 3.62-3.45 (m, 2H), 2.99 (s,3H), 2.79 (s, 3H), 2.25-2.10 (m, 2H); Anal. Calcd. for C₂₂H₂₈F₂N₈O₄S: C,49.1; H, 5.2; N, 20.8. Found: C, 49.2; H, 5.3; 20.8%.

Example 38 Synthesis ofN-{(3S)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]pyrrolidinyl}methanesulfonamide

Reaction of1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazolewith tert-butyl(3S)-pyrrolidinylcarbamate as in Example 36 gavetert-butyl(3S)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]pyrrolidinylcarbamatein 91% yield as a white solid: mp (CH₂Cl₂/MeOH) 292° C. dec.; ¹H NMR(DMSO-d₆) δ8.01 and 7.98 (2d, J=8.2, 8.4 Hz, 1H), 7.77 and 7.75 (2t,J_(HF)=53.0 Hz, 1H), 7.40 (2t, J=8.2 Hz, 1H), 7.21 (br, exchangeablewith D₂O, 1H), 6.95 (d, J=8.0 Hz, 1H), 4.15-411 (m, 1H), 3.97 (s, 3H),3.79-3.37 (m, 12H), 3.00-2.08 and 1.95-1.05 (2m, 2H), 1.40 (s, 9H).

Deprotection of the carbamate with TFA in CH₂Cl₂ gave(3S)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-pyrrolidinaminein 95% yield.

Reaction of(3S)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-pyrrolidinaminewith methanesulfonyl chloride as in Example 28 gaveN-{(3S)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]pyrrolidinyl}methanesulfonamidein 87% yield: mp (CH₂Cl₂/MeOH) 290-292° C.; ¹H NMR (DMSO-d₆) δ8.00 (t,J=8.7 Hz, 1H), 7.77 and 7.76 (2t, J_(HF)=53.0 Hz, 1H), 7.44 (br s, 1H),7.40 (dt, J=8.3, 2.5 Hz, 1H), 6.95 (d, J=8.0 Hz, 1H), 4.12-4.02 (m, 1H),3.98 (s, 3H), 3.90-3.45 (m, 12H), 3.00 and 2.99 (2s, 3H), 2.30-2.19 and2.03-1.93 (m, 2H); Anal. Calcd. for C₂₁H₂₆F₂N₈O₄S: C, 48.1; H, 5.0; N,21.4. Found: C, 48.2; H, 5.0; N, 21.3%.

Example 39 Synthesis ofN-{(3S)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]pyrrolidinyl}-N-methylmethanesulfonamide

Methylation ofN-{(3S)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]pyrrolidinyl}methanesulfonamide(Example 38) with iodomethane in the presence of K₂CO₃ in DMF as inExample 31 gaveN-{(3S)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]pyrrolidinyl}-N-methylmethanesulfonamidein 98% yield: mp (CH₂Cl₂/MeOH) 244-247° C.; ¹H NMR (DMSO-d₆) δ8.01 and8.00 (2d, J=8.2 Hz, 1H), 7.78 and 7.77 (2t, J=53.0 Hz, 1H), 7.41 (dt,J=8.3, 2.2 Hz, 1H), 6.95 (d, J=8.0 Hz, 1H), 4.57-4.46 (m, 1H), 3.98 (s,3H), 3.92-3.82 (m, 6H), 3.70-3.69 (m, 4H), 3.62-3.45 (m, 2H), 2.99 (s,3H), 2.79 (s, 3H), 2.25-2.10 (m, 2H); Anal. Calcd. for C₂₂H₂₈F₂N₈O₄S: C,49.1; H, 5.2; N, 20.8. Found: C, 49.3; H, 5.3; 20.8%.

Example 40 Synthesis of4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[(3R)-1-(methylsulfonyl)piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine

Reaction of1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazolewith tert-butyl(3R)-3-amino-1-piperidinecarboxylate as in Example 28gavetert-butyl(3R)-3-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}-1-piperidinecarboxylatein 88% yield: ¹H NMR (DMSO-d₆) (rotamers) δ8.11 and 8.00 (2d, J=8.1, 8.2Hz, 1H), 7.89 and 7.71 (2t, J_(HF)=53.1 Hz, 1H), 7.38 (t, J=8.2 Hz, 1H),6.95 and 6.94 (2d, J=8.0, 7.8 Hz, 1H), 3.97 (s, 3H), 3.79-3.69 (m, 10H),3.02-2.80 (m, 2H), 1.97-1.93 (m, 1H), 1.76 (m, 1H), 1.59-1.20 (m, 2H),1.35 (s, 9H). Anal. Calcd. for C₂₆H₃₄F₂N₈O₄: C, 55.7; H, 6.1; N, 20.0.Found: C, 55.9; H, 6.1; N, 20.1%.

Deprotection of the above carbamate with TFA in CH₂Cl₂ gave4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-[(3R)-piperidinyl]-1,3,5-triazin-2-aminein 98% yield: ¹H NMR (DMSO-d₆) (rotamers) δ8.10 and 7.93 (2d, J=8.3 Hz,1H), 7.88 and 7.73 (2t, J_(HF)=53.0 Hz, 1H), 7.84 and 7.91 (2d, J=7.7,7.9 Hz, 1H), 7.43-7.36 (m, 1H), 6.95 and 6.94 (2d, J=7.9 Hz, 1H), 3.98and 3.97 (2s, 3H), 3.93-3.91 (m, 1H), 3.79 (m, 4H), 3.69 (m, 4H),3.18-3.09 (m, 1H), 2.93-2.89 (m, 1H), 2.60-2.52 (m, 2H), 1.96-1.94 and1.73-1.70 (2m, 2H), 1.56-1.42 (m, 2H).

Reaction of4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-[(3R)-piperidinyl]-1,3,5-triazin-2-aminewith methanesulfonyl chloride as in Example 28 gave4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[(3R)-1-(methylsulfonyl)piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-aminein 76% yield: mp (CH₂Cl₂/MeOH) 241-243° C.; ¹H NMR (DMSO-d₆) δ8.11-7.90(m, 2H), 7.88 and 7.38 (2t, J_(HF)=53.1, 53.0 Hz, 1H), 7.38 (t, J=8.2Hz, 1H), 6.94 (d, J=8.1 Hz, 1H), 4.04-3.68 (m, 10H), 3.97 (s, 3H), 3.48(m, 1H), 2.88 (s, 3H), 2.82-2.75 (m, 1H), 2.70-2.52 (m, 1H), 1.97-1.87(m, 2H), 1.68-1.47 (m, 2H); Anal. Calcd. for C₂₂H₂₈F₂N₈O₄S: C, 49.1; H,5.2; N, 20.8. Found: C, 49.3; H, 5.3; N, 20.8%.

Example 41 Synthesis of4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-methyl-N-[(3R)-1-(methylsulfonyl)piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine

Methylation of4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[(3R)-1-(methylsulfonyl)piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine(Example 40) with iodomethane in the presence of NaH in DMF as inExample 29 gave4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-methyl-N-[(3R)-1-(methylsulfonyl)piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-aminein 87% yield: mp CH₂Cl₂/MeOH) 219-221° C.; ¹H NMR (DMSO-d₆) δ7.96 and7.89 (2d, J=8.3, 8.4 Hz, 1H), 7.73 and 7.65 (2t, J_(HF)=52.9, 53.0 Hz,1H), 7.41 and 7.38 (2t, J=8.2, 8.3 Hz, 1H), 6.95 (dd, J=8.1, 1.8 Hz,1H), 4.71-4.66 and 4.60-4.53 (2m, 1H), 3.98 (s, 3H), 3.81-3.56 (m, 10H),3.14 and 3.10 (2s, 3H), 2.98-2.80 (m, 1H), 2.90 (s, 3H), 2.73-2.68 (m,1H), 1.93-1.55 (m, 4H); Anal. Calcd. for C₂₃H₃₀F₂N₈O₄S: C, 50.0; H, 5.5;N, 20.3. Found: C, 50.0; H, 5.5; N, 20.5%.

Example 42 Synthesis of4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[(3S)-1-(methylsulfonyl)piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine

Reaction of1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazolewith tert-butyl(3S)-3-amino-1-piperidinecarboxylate as in Example 28gavetert-butyl(3S)-3-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}-1-piperidinecarboxylatein 90% yield: ¹H NMR (DMSO-d₆) (rotamers) δ8.12-7.58 (m, 3H), 7.38 and7.38 (2t, J=8.2 Hz, 1H), 6.95 and 6.94 (2d, J=7.8 Hz, 1H), 3.97 (s, 3H),3.78-3.69 (m, 10H), 2.99-2.94 and 2.85-2.83 (2m, 2H), 1.97-1.93 and1.78-1.76 (2m, 2H), 1.58-1.19 (m, 11H).

Deprotection of the carbamate with TFA in CH₂Cl₂ gave4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-[(3S)-piperidinyl]-1,3,5-triazin-2-aminein 100% yield: ¹H NMR (DMSO-d₆) (rotamers) δ8.78 (m, 2H), 8.11-7.59 (m,3H), 7.43-7.37 (m, 1H), 6.98-6.94 (m, 1H), 4.20-4.15 (m, 1H), 3.99 and3.97 (2s, 3H), 3.80 (m, 4H), 3.70 (m, 4H), 3.44-3.22 (m, 2H), 2.90-2.76(m, 2H), 2.04-1.91 (m, 2H), 1.77-1.53 (m, 2H).

Reaction of4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-[(3S)-piperidinyl]-1,3,5-triazin-2-aminewith methanesulfonyl chloride as in Example 28 gave4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[(3S)-1-(methylsulfonyl)piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-aminein 87% yield: mp (CH₂Cl₂/MeOH) 239-241° C.; ¹H NMR (DMSO-d₆) δ8.11-7.90(m, 2H), 7.88 and 7.69 (2t, J_(HF)=53.1, 53.0 Hz, 1H), 7.38 (t, J=8.2Hz, 1H), 6.94 (d, J=8.1 Hz, 1H), 3.97 (s, 3H), 3.94-3.68 (m, 10H),3.52-3.44 (m, 1H), 2.88 (s, 3H), 2.82-2.75 and 2.70-2.55 (2m, 2H),1.97-1.86 (m, 2H), 1.68-1.47 (m, 2H); Anal. Calcd. for C₂₂H₂₈F₂N₈O₄S: C,49.1; H, 5.2; N, 20.8. Found: C, 49.2; H, 5.4; N, 20.8%.

Example 43 Synthesis of4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-methyl-N-[(3S)-1-(methylsulfonyl)piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine

Methylation of4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[(3S)-1-(methylsulfonyl)piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-aminewith iodomethane in the presence of NaH in DMF as in Example 29 gave4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-methyl-N-[(3S)-1-(methylsulfonyl)piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-aminein 61% yield: mp (CH₂Cl₂/MeOH) 201-203° C.; ¹H NMR (DMSO-d₆) δ7.96 and7.89 (2d, J=8.3, 8.4 Hz, 1H), 7.74 and 7.65 (2t, J_(HF)=52.9 Hz, 1H),7.41 and 7.38 (t, J=8.21, 8.3 Hz, 1H), 6.95 (dd, J=8.1, 1.9 Hz, 1H),4.72-4.65 and 4.60-4.53 (2m, 1H), 3.98 (s, 3H), 3.82-3.56 (m, 10H), 3.14and 3.10 (2s, 3H), 3.00-2.80 and 2.73-2.67 (2m, 2H), 2.90 (s, 3H),1.93-1.55 (m, 4H); Anal. Calcd. for C₂₃H₃₀F₂N₈O₄S: C, 50.0; H, 5.5; N,20.3. Found: C, 50.0; H, 5.5; N, 20.6%.

Example 44 Synthesis ofN-{(3R)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]piperidinyl}methanesulfonamide

Reaction of1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazolewith tert-butyl(3R)-piperidinylcarbamate gavetert-butyl(3R)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]piperidinylcarbamatein 94% yield: mp (CH₂Cl₂/hexanes) 115-118° C.; ¹H NMR (DMSO-d₆)(rotamers) δ8.00 and 7.89 (2d, J=8.1, 8.4 Hz, 1H), 7.72 and 7.69 (t,J_(HF)=52.6, 52.7 Hz, 1H), 7.43-7.36 (m, 1H), 6.95 (d, J=7.9 Hz, 1H),6.95 (br, exchangeable with D₂O, 1H), 4.53-4.43, 4.37-4.31 and 4.21-4.13(3m, 1H), 3.97 (s, 3H), 3.79 (m, 4H), 3.69 (m, 4H), 3.42-3.36 (m, 2H),3.16-3.10 and 3.02-2.96 (2m, 2H) 1.88-1.79 (m, 2H), 1.55-1.40 (m, 2H),1.40 and 1.38 (2s, 9H).

Deprotection of the above carbamate with TFA in CH₂Cl₂ gave(3R)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-piperidinaminein 96% yield: ¹H NMR (DMSO-d₆) δ7.88 (d, J=8.2 Hz, 1H), 7.72 and 7.68(t, J_(HF)=53.4, 53.0 Hz, 1H), 7.41 (t, J=8.2 Hz, 1H), 7.41 (br,exchangeable with D₂O, 2H), 6.96 (d, J=8.2 Hz, 1H), 4.49-4.38 (m, 1H),4.22-4.14 and 3.90 (2m, 2H), 3.98 (s, 3H), 3.81 (m, 4H), 3.70 (m, 4H),3.94-3.40 (m, 2H), 2.03-2.00 and 1.81 (2m, 2H), 1.66-1.54 (m, 2H).

Reaction of(3R)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-piperidinaminewith methanesulfonyl chloride as in Example 28 gaveN-{(3R)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]piperidinyl}methanesulfonamidein 90% yield: mp (CH₂Cl₂/MeOH) 220-221° C.; ¹H NMR (DMSO-d₆) δ7.98 and7.88 (2d, J=8.4 Hz, 1H), 7.70 and 7.68 (2t, J_(HF)=52.9 Hz, 1H), 7.41and 7.37 (2t, J=8.2, 8.1 Hz, 1H), 7.30-7.27 (m, 1H), 6.96 (d, J=8.1 Hz,1H), 4.55 and 4.52 (2d, J=3.3 Hz, 1H), 4.36-4.33 and 4.26-4.23 (2m, 1H),3.97 (s, 3H), 3.80 (m, 4H), 3.69 (m, 4H), 3.39-3.10 (m, 2H), 2.95 (s,3H), 1.98 and 1.80-1.78 ((2m, 2H), 1.69-1.49 (m, 2H); Anal. Calcd. forC₂₂H₂₈F₂N₈O₄S: C, 49.1; H, 5.2; N, 20.8. Found: C, 49.0; H, 5.3; N,20.8%.

Example 45 Synthesis ofN-{(3R)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]piperidinyl}-N-methylmethanesulfonamide

Methylation ofN-{(3R)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]piperidinyl}methanesulfonamide(Example 44) with iodomethane in the presence of K₂CO₃ in DMF as inExample 31 gaveN-{(3R)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]piperidinyl}-N-methylmethanesulfonamidein 93% yield: mp (CH₂Cl₂/MeOH) 224-226° C.; ¹H NMR (DMSO-d₆) δ7.92 and7.88 (2d, J=8.3 Hz, 1H), 7.68 and 7.67 (2t, J_(HF)=52.8 Hz, 1H),7.43-7.35 (m, 1H), 6.95 (d, J=8.0 Hz, 1H), 4.69-4.54 (m, 2H), 3.97 (s.3H), 3.80-3.59 (m, 9H), 3.18-3.08 (m, 1H), 2.96 and 2.93 (2s, 3H),2.90-2.87 (m, 1H), 2.83 and 2.82 (2s, 3H), 1.86-1.57 (m, 4H); Anal.Calcd. for C₂₃H₃₀F₂N₈O₄S: C, 50.0; H, 5.5; N, 20.3. Found: C, 49.8; H,5.4; N, 20.4%.

Example 46 Synthesis ofN-{(3S)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]piperidinyl}methanesulfonamide

Reaction of1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazoleand tert-butyl(3S)-piperidinylcarbamate gavetert-butyl(3S)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]piperidinylcarbamatein 100% yield: mp (CH₂Cl₂/hexanes) 119-122° C.; ¹H NMR (DMSO-d₆)(rotamers) δ8.00 and 7.89 (2d, J=8.4, 8.3 Hz, 1H), 7.72 and 7.69 (2t,J_(HF)=52.9 Hz, 1H), 7.43-7.36 (m, 1H), 6.95 (d, J=7.9 Hz, 1H), 6.96(br, exchangeable with D₂O, 1H), 4.51-4.80, 4.37-4.34, and 4.21-4.14(3m, 1H), 3.97 (s, 3H), 3.79 (m, 4H), 3.69 (m, 4H), 3.42-3.39 and 3.28(2m, 2H), 3.17-3.10 and 3.02-2.96 (2m, 2H), 1.88-1.74 (m, 2H), 1.53-1.44(m, 2H), 1.40 and 1.38 (2s, 9H).

Deprotection of the above carbamate with TFA in CH₂Cl₂ gave(3S)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-piperidinaminein 100% yield: ¹H NMR (DMSO-d₆) (rotamers) δ7.88 (d, J=8.3 Hz, 1H), 7.72and 7.68 (2t, J_(HF)=53.0 Hz, 1H), 7.41 (t, J=8.2 Hz, 1H), 6.96 (d,J=8.1 Hz, 1H), 6.71 (br, exchangeable with D₂O, 2H), 4.52-4.35 (m, 1H),4.25-4.16 and 3.10 (2m, 2H), 3.98 (s, 3H), 3.81 (m, 4H), 3.70 (m, 4H),3.28 (m, 2H), 1.99 and 1.81 (2m, 2H), 1.55 (m, 2H).

Reaction of(3S)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-piperidinaminewith methanesulfonyl chloride as in Example 28 gaveN-{(3S)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]piperidinyl}methanesulfonamidein 79% yield: mp (CH₂Cl₂/MeOH) 220-221° C.; ¹H NMR (DMSO-d₆) δ7.98 and7.88 (2d, 1H), 7.70 and 7.68 (2t, J_(HF)=52.8, 53.0 Hz, 1H), 7.41 and7.37 (2t, J=8.0, 8.2 Hz, 1H), 7.30-7.26 (m, 1H), 6.94 (d, J=8.1 Hz, 1H),4.55 and 4.52 2 (d, J=3.6, 3.3 Hz, 1H), 4.36-4.33 and 4.26-4.23 (2m,2H), 3.97 (s, 3H), 3.80 (m, 4H), 3.69 (m, 4H), 3.39-3.10 (m, 2H), 2.95(s, 3H), 1.98 and 1.81-1.78 (2m, 2H), 1.60-1.51 (m, 2H); Anal. Calcd.for C₂₂H₂₈F₂N₈O₄S: C, 49.1; H, 5.2; N, 20.8. Found: C, 49.2; H, 5.2; N,20.8%.

Example 47 Synthesis ofN-{(3S)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]piperidinyl}-N-methylmethanesulfonamide

Methylation ofN-{(3S)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]piperidinyl}methanesulfonamide(Example 46) with iodomethane in the presence of K₂CO₃ in DMF as inExample 31 gaveN-{(3S)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]piperidinyl}-N-methylmethanesulfonamidein 91% yield: mp (CH₂Cl₂/MeOH) 221-223° C.; ¹H NMR (DMSO-d₆) δ7.92 and7.88 (2d, J=8.3, 8.4 Hz, 1H), 7.68 and 7.67 (2t, J_(HF)=52.9, 52.7 Hz,1H), 7.43-7.35 (m, 1H), 6.95 (d, J=8.1 Hz, 1H), 4.69-4.55 (m, 2H), 3.97(s, 3H), 3.80-3.60 (m, 9H), 3.18-3.08 (m, 1H), 2.96 and 2.94 (2s, 3H),2.90-2.87 (m, 1H), 2.83-2.82 (2s, 3H), 1.88-1.83 and 1.60-1.53 (2m, 4H);Anal. Calcd. for C₂₃H₃₀F₂N₈O₄S: C, 50.0; H, 5.5; N, 20.3. Found: C,49.9; H, 5.5; N, 20.5%.

Example 48 Synthesis of2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[2-(1-oxido-4-thiomorpholinyl)ethyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole

A mixture of2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(vinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole(Example 3) (200 mg, 0.373 mmol), thiomorpholine 1-oxidetrifluoroacetate (U.S. Pat. No. 6,372,773) (242 mg, 1.12 mmol), andDIPEA (0.45 mL, 2.61 mmol) was refluxed in THF (60 mL) for 4 days. TheTHF was removed under vacuum and the residue was dissolved in dioxane(60 mL). Additional thiomorpholine 1-oxide trifluoroacetate (161 mg,0.745 mmol) and DIPEA (0.45 mL, 2.61 mmol) were added and the mixturewas refluxed for 2 days. The solvent was removed under vacuum and theresidue was diluted with water. The resulting precipitate was filtered,washed with water, and dissolved in CH₂Cl₂. The solution was dried(Na₂SO₄) and the solvent was removed under vacuum. Chromatography onsilica, eluting with CH₂Cl₂/MeOH (95:5), followed by recrystallizationfrom CH₂Cl₂/hexane gave 138 mg (56% yield) of2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[2-(1-oxido-4-thiomorpholinyl)ethyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole:mp (CH₂Cl₂/hexane) 229-231° C.; ¹H NMR (CDCl₃) δ7.85 (d, J=8.0 Hz, 1H),7.43 (t, J_(HF)=53.5 Hz, 1H), 7.36 (t, J=8.2 Hz, 1H), 6.82 (d, J=7.9 Hz,1H), 4.05 (s, 3H), 4.01 (br s, 4H), 3.89 (br s, 4H), 3.79 (m, 4H), 3.38(t, J=5.0 Hz, 4H), 3.15 (m, 4H), 2.99 (dd, J=8.8, 5.4, 2H), 2.79 (m,6H); Anal. Calcd. for C₂₆H₃₅F₂N₉O₅S₂.0.2H₂O: C, 47.4; H, 5.4; N, 19.1.Found: C, 47.3; H, 5.5; N, 18.7.

Example 49 Synthesis of2-(difluoromethyl)-1-[4-(4-{[2-(1,1-dioxido-4-thiomorpholinyl)ethyl]sulfonyl}-1-piperazinyl)-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-methoxy-1H-benzimidazole

A mixture of2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(vinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole(Example 3) (180 mg, 0.335 mmol), thiomorpholine (0.17 mL, 1.68 mmol) inTHF (50 mL) was stirred at room temperature for 3 days and then atreflux for 3 hrs. The solvent was removed under vacuum and the residuewas dissolved in dioxane (30 mL) and additional thiomorpholine (0.17 mL,1.68 mmol) was added. The reaction mixture was refluxed for 2 days. Thesolvent was removed under vacuum and the residue diluted with water. Theresulting precipitate was filtered, washed with water and dissolved inCH₂Cl₂. The solution was dried (Na₂SO₄) and solvent removed undervacuum. Chromatography on silica, eluting with CH₂Cl₂/MeOH (98:2),followed by recrystallization from CH₂Cl₂/hexane gave 180 mg (84% yield)of2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[2-(4-thiomorpholinyl)ethyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole:mp (CH₂Cl₂/hexane) 210-212° C.; ¹H NMR (CDCl₃) δ7.86 (dd, J=8.3, 0.5 Hz,1H), 7.43 (t, J_(HF)=53.5 Hz, 1H), 7.36 (t, J=8.2 Hz, 1H), 6.82 (d,J=7.7 Hz, 1H), 4.05 (s, 3H), 4.00 (br s, 4H), 3.89 (br s, 4H), 3.79 (m,4H), 3.38 (t, J=5.1 Hz, 4H), 3.11 (dd, J=8.3, 6.1 Hz, 2H), 2.87 (dd,J=8.3, 6.1 Hz, 2H), 2.73 (dd, J=6.1, 3.8 Hz, 4H), 2.63 (m, 4H); Anal.Calcd. for C₂₆H₃₅F₂N₉O₄S₂.0.5H₂O: C, 48.1; H, 5.6; N, 19.4. Found: C,48.2; H, 5.4; N, 19.3%.

A solution of KMnO₄ (88 mg, 0.559 mmol) in water (6 mL) was addeddropwise to a stirred solution of2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[2-(4-thiomorpholinyl)ethyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole(170 mg, 0.266 mmol) in acetone (50 mL) and acetic acid (7.5 mL) at roomtemperature. After 2.5 hrs the reaction was diluted with water,decolourized with Na₂SO₃ and the acetone removed under vacuum. Themixture was neutralized with conc. aq. NH₃ to give a precipitate, whichwas dissolved in CH₂Cl₂ and dried (Na₂SO₄). The solvent was then removedunder vacuum. Chromatography on silica, eluting with CH₂Cl₂/MeOH(98.5:1.5) gave 117 mg (65% yield) of2-(difluoromethyl)-1-[4-(4-{[2-(1,1-dioxido-4-thiomorpholinyl)ethyl]sulfonyl}-1-piperazinyl)-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-methoxy-1H-benzimidazole:mp 258-261° C.; ¹H NMR (CDCl₃) δ7.85 (d, J=8.3 Hz, 1H), 7.42 (t,J_(HF)=53.5 Hz, 1H), 7.35 (t, J=8.2 Hz, 1H), 6.82 (d, J=8.0 Hz, 1H),4.05 (s, 3H), 4.01 (br s, 4H), 3.88 (br s, 4H), 3.79 (m, 4H), 3.37 (t,J=5.0 Hz, 4H), 3.07 (m, 4H), 3.05 (s, 8H); HRMS Calcd. forC₂₆H₃₆F₂N₉O₆S₂: MH⁺ m/z 672.2198. Found: m/z 672.2184.

Example 50 Synthesis ofN-{2-[(4-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]oxy}-1-piperidinyl)sulfonyl]ethyl}-N,N-dimethylamine

To a solution of2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-piperidinyloxy)-1,3,5-triazin-2-yl]-1H-benzimidazole(Example 16) (1.52 g, 3.29 mmol) and DIPEA (2.3 ml, 4 eq.) in CH₂Cl₂ (30mL) at 0° C. was added 2-chloroethanesulfonyl chloride (1 mL, excess).The reaction mixture was stirred at 20° C. for 20 hrs and diluted withwater (50 mL). The CH₂Cl₂ layer was separated and the aqueous layer wasfurther extracted with CH₂Cl₂ (3×20 mL). The combined organic fractionswere washed successively with aq. HOAc, aq. K₂CO₃, and water, and dried(MgSO₄). Evaporation of the solvent and chromatography of the residue onsilica, eluting with CH₂Cl₂/EtOAc (9:1) gave2-(difluoromethyl)-4-methoxy-1-(4-(4-morpholinyl)-6-{[1-(vinylsulfonyl)-4-piperidinyl]oxy}-1,3,5-triazin-2-yl)-1H-benzimidazole(1.17 g, 65% yield): mp (CH₂Cl₂/MeOH) 266-269° C.; ¹H NMR (DMSO-d₆)δ7.95 (d, J=7.9 Hz, 1H), 7.70 (t, J_(HF)=52.8 Hz, 1H), 7.44 (t, J=8.2Hz, 1H), 6.98 (d, J=7.8 Hz, 1H), 6.88 (dd, J=16.5, 10.0 Hz, 1H), 6.19(d, J=10.0 Hz, 1H), 6.15 (d, J=16.5 Hz, 1H), 5.26-5.20 (m, 1H), 3.98 (s,3H), 3.84 (m, 4H), 3.74-3.32 (m, 4H), 3.39-3.32 (m, 2H), 3.14-3.08 (m,2H), 2.14-2.09 (m, 2H), 1.90-1.18 (m, 2H); Anal. Calcd. forC₂₃H₂₇F₂N₇O₅S.0.5CH₂Cl₂: C, 47.7; H, 4.7; N, 16.5. Found: C, 47.8; H,4.7; N, 16.8%.

To a suspension of the above vinylsulfone (207 mg, 0.38 mmol) in THF (25mL) was added 40% aq. dimethylamine (5 mL, excess) and the reactionmixture was stirred at 20° C. for 20 hrs. The solvent was evaporated andthe residue was diluted with H₂O (50 mL). The resulting precipitate wasfiltered, washed with water and dried. Chromatography on silica, elutingwith CH₂Cl₂/MeOH (97:3) gaveN-{2-[(4-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]oxy}-1-piperidinyl)sulfonyl]ethyl}-N,N-dimethylamine(210 mg, 97% yield). The amine was converted to the hydrochloride saltby combining with 1.25 M HCl in MeOH: mp (MeOH), 264-268° C.; ¹H NMR(DMSO-d₆) δ10.20 (br s, 1H), 7.96 (d, J=7.9 Hz, 1H), 7.72 (t,J_(HF)=52.8 Hz, 1H), 7.45 (t, J=8.3 Hz, 1H), 6.99 (d, J=7.8 Hz, 1H),5.30-5.24 (m, 1H), 3.90 (s, 3H), 3.86-3.83 (m, 4H), 3.74-3.71 (m, 4H),3.64-3.60 (m, 2H), 3.54-3.49 (m, 2H), 3.42-3.39 (m, 2H), 3.32-3.24 (m,2H), 2.80 (s, 6H), 2.16-2.09 (m. 2H), 1.92-1.84 (m, 2H); Anal. Calcd.for C₂₅H₃₅ClF₂N₈O₅S: C, 47.3; H, 5.6; N, 17.7; Cl, 5.6. Found: C, 47.4;H, 5.7; N, 17.8; Cl, 5.7%.

Example 51 Synthesis of2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[(1-{[2-(4-morpholinyl)ethyl]sulfonyl}-4-piperidinyl)oxy]-1,3,5-triazin-2-yl}-1H-benzimidazole

The title compound was made according to the procedure as described inExample 50.

Reaction of2-(difluoromethyl)-4-methoxy-1-(4-(4-morpholinyl)-6-{[1-(vinylsulfonyl)-4-piperidinyl]oxy}-1,3,5-triazin-2-yl)-1H-benzimidazole(Example 50) with morpholine as in Example 11 gave2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[(1-{[2-(4-morpholinyl)ethyl]sulfonyl}-4-piperidinyl)oxy]-1,3,5-triazin-2-yl}-1H-benzimidazolein 81% yield. Hydrochloride: mp (MeOH) 255-259° C.; ¹H NMR (DMSO-d₆)δ10.87 (br s, 1H), 7.96 (d, J=8.3 Hz, 1H), 7.72 (t, J_(HF)=52.8 Hz, 1H),7.45 (t, J=8.3 Hz, 1H), 6.99 (d, J=7.8 Hz, 1H), 5.30-5.25 (m, 1H),4.06-3.95 (m, 2H), 3.98 (s, 3H), 3.86-3.84 (m, 4H), 3.74-3.71 (m, 8H),3.53-3.49 (m, 6H), 3.37-3.27 (m, 2H), 3.15 (m, 2H), 2.16-2.15 (m, 2H),2.19-1.87 (m, 2H); Anal. Calcd. for C₂₇H₃₇ClF₂N₈O₆S.0.1H₂O: C, 47.9; H,5.5; N, 16.6; Cl, 5.2. Found: C, 47.9; H, 5.6; N, 16.6; Cl, 5.5%.

Example 52 Synthesis of2-(difluoromethyl)-4-methoxy-1-[4-{[1-({2-[4-(methylsulfonyl)-1-piperazinyl]ethyl}sulfonyl)-4-piperidinyl]oxy}-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole

The title compound was made according to the procedure as described inExample 50.

Reaction of2-(difluoromethyl)-4-methoxy-1-(4-(4-morpholinyl)-6-{[1-(vinylsulfonyl)-4-piperidinyl]oxy}-1,3,5-triazin-2-yl)-1H-benzimidazolewith 1-(methylsulfonyl)piperazine as in Example 12 gave2-(difluoromethyl)-4-methoxy-1-[4-{[1-({2-[4-(methylsulfonyl)-1-piperazinyl]ethyl}sulfonyl)-4-piperidinyl]oxy}-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazolein 28% yield: mp (MeOH) 251-254° C.; ¹H NMR(DMSO-d₆) δ7.96 (d, J=8.3 Hz,1H), 7.71 (t, J_(HF)=52.8 Hz, 1H), 7.45 (t, J=8.3 Hz, 1H), 6.99 (d,J=7.9 Hz, 1H), 5.28-5.22 (m, 1H), 3.98 (s, 3H), 3.85-3.84 (m, 4H),3.74-3.70 (m, 4H), 3.52-3.46 (m, 2H), 3.34-3.20 (m, 4H), 3.13-3.11 (m,4H), 2.86 (s, 3H), 2.78-2.74 (m, 2H), 2.56-2.54 (m, 4H), 2.13-2.08 (m,2H), 1.88-1.80 (m, 2H); Anal. Calcd. for C₂₈H₃₉F₂N₉O₇S₂: C, 47.0; H,5.5; N, 17.6. Found: C, 47.2; H, 5.4; N, 17.4%.

Example 53 Synthesis ofN-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}-N-[3-(dimethylamino)propyl]-methanesulfonamide

To a mixture ofN-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}methanesulfonamide(Example 17) (1.95 g, 3.62 mmol) and K₂CO₃ (6 g, excess) in DMF (20 mL)was added 3-bromo-1-propanol (4 mL, excess). The reaction mixture wasstirred at 20° C. for 7 days and diluted with water. The resultingsticky material was extracted into CH₂Cl₂ (4×30 mL) and dried (Na₂SO₄).Evaporation of the solvent and the chromatography of the residue onsilica, eluting with a gradient of CH₂Cl₂ and EtOAc (0-20%) followed byCH₂Cl₂/MeOH (97:3) gaveN-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}-N-(3-hydroxypropyl)methanesulfonamide(1.04 g, 49%): mp (CH₂Cl₂/MeOH) 219-221° C.; ¹H NMR (DMSO-d₆) δ7.89 (d,J=8.2 Hz, 1H), 7.69 (t, J_(HF)=52.9 Hz, 1H), 7.41 (t, J=8.2 Hz, 1H),6.95 (d, J=7.9 Hz, 1H), 4.73 (d, J=12.8 Hz, 1H), 4.82 (d, J=12.3 Hz,1H), 4.44 (t, J=5.1 Hz, 1H), 3.97 (S, 3H), 3.92-3.83 (m, 1H), 3.80-3.79(m, 4H), 3.69 (m, 4H), 3.40-3.32 (m, 2H), 3.14-2.96 (m, 4H), 3.96 (s,3H), 1.87-1.80 (m, 2H), 1.74-1.64 (m, 4H); Anal Calcd. forC₂₅H₃₄F₂N₈O₅S: C, 50.33; H, 5.74; N, 18.78. Found: C, 50.2; H, 5.9; N,18.5%.

The above alcohol (305 mg, 0.51 mmol) in CH₂Cl₂ (15 mL) was treated withEt₃N (0.3 mL) and methanesulfonyl chloride (0.2 mL, 2.5 mmol) at 0° C.The reaction mixture was stirred at this temp for 45 min and 40% aqueoussolution of dimethylamine (5 mL) was then added. Stirring was continuedfor 2 days at 20° C., and the CH₂Cl₂ was evaporated. The residue wasdiluted with water, and the resulting precipitate was washed with waterand dried. Chromatography on neutral alumina, eluting with CH₂Cl₂/MeOH(98:2), followed by chromatography on silica, eluting withCH₂Cl₂/MeOH/aq. NH₃ (96:3:1) gaveN-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}-N-[3-(dimethylamino)propyl]methanesulfonamide(200 mg, 63%). The amine was converted to the hydrochloride salt bycombining with 1.25 M HCl in MeOH. Recrystallization fromMeOH/isopropanol gaveN-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}-N-[3-(dimethylamino)propyl]methanesulfonamidehydrochloride: mp 187-191° C.; ¹H NMR (DMSO-d₆) δ9.83 (br s, 1H), 7.89(d, J=8.0 Hz, 1H), 7.70 (t, J_(HF)=52.9 Hz, 1H), 7.41 (t, J=8.2 Hz, 1H),6.95 (d, J=7.9 Hz, 1H), 4.84-4.73 (m, 2H), 3.98 (s, 3H), 3.92-3.85 (m,1H), 3.80 (m, 4H), 3.70 (m, 4H), 3.16 (t, J=7.4 Hz, 2H), 3.11-2.96 (m,7H), 2.71 (s, 6H), 1.91-1.83 (m, 4H), 1.73-1.68 (m, 2H); Anal. Calcd.for C₂₇H₄₀ClF₂N₉O₄S.H₂O: C, 47.8; H, 6.2; N, 18.6; Cl, 5.2. Found: C,47.9; H, 6.2; N, 18.6; Cl, 5.0%.

Example 54 Synthesis ofN-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}-N-[3-(4-morpholinyl)propyl]-methanesulfonamide

Reaction ofN-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}-N-(3-hydroxypropyl)methanesulfonamidewith methanesulfonyl chloride as in Example 53, followed by reactionwith morpholine for 10 days at room temperature, gaveN-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}-N-[3-(4-morpholinyl)propyl]methanesulfonamidein 58% yield. Hydrochloride: mp (MeOH) 229-231° C.; ¹H NMR (DMSO-d₆)δ10.23 (br s, 1H), 7.89 (d, J=8.0 Hz, 1H), 7.70 (t, J_(HF)=52.9 Hz, 1H),7.41 (t, J=8.2 Hz, 1H), 6.95 (d, J=7.8 Hz, 1H), 4.84-4.74 (m, 2H), 3.98(s, 3H), 3.95-3.85 (m, 3H), 3.80 (m, 4H), 3.73-3.67 (m, 6H), 3.39-3.29(m, 2H), 3.17 (t, J=7.2 Hz, 2H), 3.11-2.99 (m, 9H), 1.94-1.84 (m, 4H),1.72-1.70 (m, 2H); Anal. Calcd. for C₂₉H₄₂ClF₂N₉O₅S.0.75H₂O: C, 48.7; H,6.1; N, 17.6; Cl, 5.0. Found: C, 48.7; H, 6.2; N, 17.6; Cl, 4.9%.

Example 55 Synthesis of2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[2-(1-pyrrolidinyl)ethyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole

A mixture of2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(vinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole(Example 3) (150 mg, 0.280 mmol) and pyrrolidine (0.23 mL, 2.80 mmol) in1,4-dioxane (20 mL) was stirred at room temperature for 16 hrs and thenrefluxed for 3 hrs. The solvent was removed under vacuum, the residuewas diluted with water and the resulting precipitate was dissolved inCH₂Cl₂. The organic layer was separated and dried (Na₂SO₄), and solventwas removed under vacuum. Chromatography on silica eluting withCH₂Cl₂/MeOH (98:2), followed by recrystallization from CH₂Cl₂/hexanesgave2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[2-(1-pyrrolidinyl)ethyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole(137 mg, 81%): mp 186-188° C.; ¹H NMR (CDCl₃) δ7.86 (dd, J=8.4, 0.6 Hz,1H), 7.44 (t, J_(HF)=53.5 Hz, 1H), 7.35 (t, J=8.2 Hz, 1H), 6.82 (d,J=7.6 Hz, 1H), 4.05 (s, 3H), 3.99 (br s, 4H), 3.88 (br s, 4H), 3.79 (m,4H), 3.39 (t, J=5.0 Hz, 4H), 3.16 (m, 2H), 2.93 (m, 2H), 2.53 (m, 4H),1.76 (m, 4H); Anal. Calcd. for C₂₆H₃₅F₂N₉O₄S: C, 51.4; H, 5.8; N, 20.7.Found: C, 51.3; H, 5.9; N, 20.5%.

Example 56 Synthesis of3-[2-({4-[4-[2-(Difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)ethyl]-8-oxa-3-azabicyclo[3.2.1]octane

A mixture of2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(vinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole(Example 3) (150 mg, 0.280 mmol), 8-oxa-3-azoniabicyclo[3.2.1]octanehydrochloride (209 mg, 1.40 mmol), and DIPEA (0.49 mL, 2.80 mmol) in1,4-dioxane was stirred at room temperature for 2.5 days. Additional8-oxa-3-azoniabicyclo[3.2.1]octane hydrochloride (84 mg, 0.561 mmol) wasadded and the mixture refluxed for 1 hr. The solvent was removed undervacuum, and the residue was diluted with water. The resultingprecipitate was dissolved in CH₂Cl₂ and dried (Na₂SO₄). The solvent wasremoved under vacuum. Chromatography on silica eluting with CH₂Cl₂/MeOH(98:2), followed by recrystallization from CH₂Cl₂/hexanes gave3-[2-({4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)ethyl]-8-oxa-3-azabicyclo[3.2.1]octane(118 mg, 87%): mp 219-221° C.; ¹H NMR (CDCl₃) δ7.85 (dd, J=8.4, 0.5 Hz,1H), 7.43 (t, J_(HF)=53.5 Hz, 1H), 7.36 (t, J=8.2 Hz, 1H), 6.82 (d,J=7.7 Hz, 1H), 4.26 (m, 2H), 4.05 (s, 3H), 4.01 (br s, 4H), 3.88 (br s,4H), 3.79 (m, 4H), 3.38 (t, J=5.0 Hz, 4H), 3.07 (dd, J=8.1, 6.3 Hz, 2H),2.79 (dd, J=8.1, 6.3 Hz, 2H), 2.55 (d, J=10.6 Hz, 2H), 2.38 (dd, J=10.9,2.0 Hz, 2H), 1.83 (m, 4H); Anal. Calcd. for C₂₈H₃₇F₂N₉O₅S: C, 51.8; H,5.7; N, 19.4. Found: C, 51.8; H, 5.9; N, 19.3%.

Example 57 Synthesis ofN-[3-({4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)propyl]-N,N-dimethylamine

A mixture of2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole(Example 2) (150 mg, 0.378 mmol),N,N-dimethyl-3-(1-piperazinylsulfonyl)-1-propanamine dihydrochloride (WO2006/046040) (151 mg, 0.491 mmol), and DIPEA (0.40 mL, 2.27 mmol) inDMSO was stirred at room temperature for 30 minutes. The reactionmixture was diluted with water; and the resulting precipitate wascollected by filtration, washed with water, and dissolved in CH₂Cl₂. Thesolution was dried (Na₂SO₄) and the solvent removed under vacuum.Chromatography on silica eluting with CH₂Cl₂/MeOH (95:5), followed byadditional chromatography on silica eluting with CH₂Cl₂/MeOH (96:4) gaveN-[3-({4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)propyl]-N,N-dimethylamine(91 mg, 40%). Treatment with 1.25 M HCl solution in MeOH andrecrystallization from MeOH/EtOAc gave the hydrochloride salt: mp209-211° C.; ¹H NMR (DMSO-d₆) δ10.16 (br s, 1H), 7.89 (d, J=8.4 Hz, 1H),7.69 (t, J_(HF)=52.9 Hz, 1H), 7.41 (t, J=8.2 Hz, 1H), 6.96 (d, J=7.8 Hz,1H), 3.98 (s, 3H), 3.94 (m, 4H), 3.82 (m, 4H), 3.70 (br s, 4H), 3.33 (m,4H), 3.23 (dd, J=9.3, 5.8 Hz, 2H), 3.12 (m, 2H), 2.75 (s, 6H), 2.08 (td,J=15.4, 7.8 Hz, 2H); Anal. Calcd. for C₂₅H₃₆ClF₂N₉O₄S.0.5H₂O: C, 46.8;H, 5.8; N, 19.7. Found: C, 46.9; H, 5.8; N, 19.4%.

Example 58 Synthesis of2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[3-(4-morpholinyl)propyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole

A mixture of2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole(Example 2) (150 mg, 0.378 mmol),4-[3-(1-piperazinylsulfonyl)propyl]morpholine dihydrochloride (WO2006/046040) (172 mg, 0.491 mmol) and DIPEA (0.40 mL, 2.27 mmol) in THFwas stirred at room temperature for 17 hrs. The solvent was removedunder vacuum, and the residue was diluted with water and extracted withCH₂Cl₂. The CH₂Cl₂ was dried (Na₂SO₄) and removed under vacuum.Chromatography on silica, eluting with CH₂Cl₂/MeOH (98:2) followed byrecrystallization from CH₂Cl₂/hexanes gave2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[3-(4-morpholinyl)propyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole(188 mg, 78%). Treatment with methanesulfonic acid in CH₂Cl₂/MeOH andrecrystallization from MeOH/EtOAc gave2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[3-(4-morpholinyl)propyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazolemethanesulfonate: mp 216-218° C.; ¹H NMR (DMSO-d₆) δ9.50 (br s, 1H),7.89 (d, J=8.2 Hz, 1H), 7.69 (t, J_(HF)=52.9 Hz, 1H), 7.41 (t, J=8.2 Hz,1H), 6.96 (d, J=7.8 Hz, 1H), 4.01-3.93 (m, 6H), 3.98 (s, 3H), 3.82 (m,4H), 3.70 (br s, 4H), 3.63 (t, J=12.1 Hz, 2H), 3.45 (d, J=12.6 Hz, 2H),3.32 (m, 4H), 3.21 (t, J=7.1 Hz, 4H), 3.09 (dd, J=21.2, 11.8 Hz, 2H),2.30 (s, 3H), 2.09 (m, 2H); Anal. Calcd for C₂₈H₄₁F₂N₉O₈S₂: C, 45.8; H,5.6; N, 17.2. Found: C, 45.7; H, 5.6; N, 17.2%.

Example 59 Synthesis ofN¹-{1-[(chloromethyl)sulfonyl]-4-piperidinyl}-N¹-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N³,N³-dimethyl-1,3-propanediamine

Reaction ofN¹-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N³,N³-dimethyl-N¹-(4-piperidinyl)-1,3-propanediamine(Example 21) with chloromethanesulfonyl chloride and K₂CO₃ in CH₂Cl₂,followed by conversion to the hydrochloride salt with 1.25 M HCl inmethanol gaveN¹-{1-[(chloromethyl)sulfonyl]-4-piperidinyl}-N¹-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N³,N³-dimethyl-1,3-propanediaminehydrochloride in 44% yield: mp (MeOH) 222-225° C.; ¹H NMR (DMSO-d₆)δ9.89 (br, 1H), 7.90 (d, J=8.4 Hz, 1H), 7.71 (t, J_(HF)=53.0 Hz, 1H),7.47-7.41 (m, 1H), 7.00 (d, J=8.2 Hz, 1H), 5.17 and 5.11 (2s, 2H),4.74-4.71 and 4.66-4.53 (2m, 1H), 3.98 (s, 3H), 3.92-3.82 (m, 6H), 3.71(m, 4H), 3.60-3.51 (m, 2H), 3.16-3.04 (m, 4H), 2.75 and 2.70 (2s, 6H),2.02-1.80 (m, 6H); Anal. Calcd. for C₂₇H₃₉Cl₂F₂N₉O₄S.0.5 H₂O: C, 46.1;H, 5.7; N, 17.9; Cl, 10.1. Found: C, 46.1; H, 5.8; N, 17.9; Cl, 9.7%.

Example 60 Synthesis ofchloro-N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}-N-[3-(dimethylamino)propyl]methanesulfonamide

To a mixture of tert-butyl4-[(3-hydroxypropyl)amino]piperidine-1-carboxylate (Yokoyama et al.,Bioorg. Med. Chem. 2008, 16, 7968) (710 mg, 2.75 mmol) and dry powderedK₂CO₃ (5.0 g, 36.0 mmol) in CH₂Cl₂ (20 mL) at 0° C. was addedchloromethanesulfonyl chloride (1 mL, excess). The reaction mixture wasstirred at 20° C. for 4 hrs, a solution of 40% aqueous dimethylamine (5mL) was then added, and stirring was continued for a further 20 hrs. Theorganic layer was separated and the aqueous layer was further extractedwith CH₂Cl₂ (2×20 mL). The combined organic fractions were washed withwater (50 mL) and dried (Na₂SO₄). The solvent was removed to give anoily product. Chromatography on neutral alumina eluting with CH₂Cl₂/MeOH(98:2) gave tert-butyl4-{[(chloromethyl)sulfonyl][3-(dimethylamino)propyl]amino}-1-piperidinecarboxylate,as an oil (946 mg, 87%): ¹H NMR (CDCl₃) δ 4.47 (s, 2H), 4.22 (br, 2H),3.82-3.75 (m, 1H), 3.31-3.27 (m, 2H), 2.28-2.46 (m, 2H), 2.76-2.70 (m,2H), 2.26 (t, J=6.9 Hz, 2H), 2.23 (s, 6H), 1.87-1.64 (m, 6H), 1.46 (s,9H).

To a solution of the above carbamate (940 mg, 2.36 mmol) in CH₂Cl₂ (10mL) was added TFA (5 mL). The reaction mixture was stirred for 1 hr.After being diluted with CH₂Cl₂ (10 mL) and H₂O (10 mL), the mixture wasmade alkaline with aqueous NH₃. The organic layer was separated and theaqueous layer was further extracted with CH₂Cl₂ (2×15 mL). The combinedorganic fractions were washed with H₂O (2×20 mL) and dried (Na₂SO₄).Evaporation of the solvent gavechloro-N-[3-(dimethylamino)propyl]-N-(4-piperidinyl)methanesulfonamide(571 mg, 81%): ¹H NMR (CDCl₃) δ 4.46 (s, 2H), 3.76-3.68 (m, 1H),3.35-3.31 (m, 2H), 3.16-3.14 (m, 2H), 2.70-2.63 (m, 2H), 2.28 (t, J=6.9Hz, 2H), 2.22 (s, 6H), 1.88-1.68 (m, 7H).

A mixture of the above amine (82 mg, 0.28 mmol),2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole(Example 2) (98 mg, 0.25 mmol), and DIPEA (0.3 mL) in THF (5 mL) wasstirred at 20° C. for 4 hrs. Most of the THF was removed under vacuumand the residue was diluted with water (20 mL). The resultingprecipitate was collected by filtration, washed with water, andchromatographed on silica eluting initially with CH₂Cl₂/EtOAc (4:1),then with CH₂Cl₂/MeOH/aqueous NH₃ (95:4:1) to givechloro-N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}-N-[3-(dimethylamino)propyl]methanesulfonamide(120 mg 74% yield), which treated with 1.25 M HCl in MeOH to give thehydrochloride salt: mp (MeOH/EtOAc) 260-263° C.; ¹H NMR (DMSO-d₆) δ10.0(br s, 1H), 7.89 (d, J=8.2 Hz, 1H), 7.70 (t, J_(HF)=52.9 Hz, 1H), 7.41(t, J=8.2 Hz, 1H), 6.95 (d, J=7.9 Hz, 1H), 5.10 (s, 2H), 4.86-4.74 (m,2H), 3.98-3.90 (m, 1H), 3.98 (s, 3H), 3.81 (m, 4H), 3.79 (m, 4H),3.24-3.25 (m, 2H), 3.11-2.96 (m, 4H), 2.70 (s, 6H), 1.93-1.75 (m, 6H);Calcd. for C₂₇H₃₉Cl₂F₂N₉O₄S.0.5H₂O: C, 46.1; H, 5.7; N, 17.9; Cl, 10.1.Found: C, 46.1; H, 5.8; N, 17.9; Cl, 9.7%.

Example 61 Synthesis ofchloro-N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}methanesulfonamide

Reaction of1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinamine(Example 17) with chloromethanesulfonyl chloride and K₂CO₃ in CH₂Cl₂gavechloro-N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}methanesulfonamidein 56% yield: mp (CH₂Cl₂/MeOH) 230-232° C.; ¹H NMR (DMSO-d₆) δ7.88 (d,J=8.0 Hz, 1H), 7.87 (br, 1H), 7.69 (t, J_(HF)=52.9 Hz, 1H), 7.41 (t,J=8.2 Hz, 1H), 6.95 (d, J=7.9 Hz, 1H), 4.95 (s, 2H), 4.59-4.49 (m, 2H),3.98 (s, 3H), 3.81-3.79 (m, 4H), 3.70-3.69 (m, 4H), 3.55 (br, 1H),3.22-3.12 (m, 2H), 1.96 (br, 2H), 1.46-1.41 (m, 2H); Anal. Calcd. forC₂₂H₂₇ClF₂N₈O4S: C, 46.1; H, 4.75; N, 19.6. Found: C, 46.4; H, 4.8; N,19.6%

Example 62 Synthesis ofchloro-N-{(3S)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-piperidinyl}methanesulfonamide

Reaction of(3S)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-piperidinamine(Example 46) with chloromethanesulfonyl chloride and K₂CO₃ in CH₂Cl₂gavechloro-N-{(3S)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-piperidinyl}methanesulfonamidein 57% yield: mp (MeOH) 166-168° C.; ¹H NMR (DMSO-d₆) (rotamers) δ7.99(br, 1H), 7.98 and 7.88 (2d, J=8.5, 8.4 Hz, 1H), 7.69 and 7.68 (2t,J_(HF)=52.9 Hz, 1H), 7.41 and 7.37 (2t, J=8.1, 8.2 Hz, 1H), 6.95 (d,J=7.9 Hz, 1H), 4.98-4.88 (m, 2H), 4.55-4.52 and 4.37-4.23 (2m, 2H), 3.97(s, 3H), 3.80 (m, 4H), 3.69 (m, 4H), 3.45-3.11 (m, 3H), 1.99 (br, 1H),1.83-1.80 (m, 1H), 1.64-1.48 (m, 2H); Anal. Calcd. forC₂₂H₂₇ClF₂N₈O₄S.0.5H₂O: C, 45.4; H, 4.85; N, 19.25. Found: C, 45.4; H,4.8; N, 19.2%.

Example 63 Synthesis ofN-{(3S)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]piperidinyl}-N-[3-(dimethylamino)propyl]methane-sulfonamide

A mixture ofN-{(3S)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]piperidinyl}methanesulfonamide(Example 46) (678 mg, 1.26 mmol), dry powdered K₂CO₃ (0.6 g, 4.3 mmol),and 3-bromopropanol (1.0 mL) in DMF (5 mL) was stirred at 20° C. for 3days. The reaction mixture was diluted with H₂O (50 mL. The resultingprecipitate was collected by filtration, washed with water, and dried.Chromatography on silica, eluting with CH₂Cl₂/EtOAc (4:1) gave partiallypurified material, which was further purified by chromatography onneutral alumina, eluting first with CH₂Cl₂/EtOAc (4:1) and then withCH₂Cl₂/MeOH (96:4) to giveN-{(3S)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]piperidinyl}-N-(3-hydroxypropyl)methanesulfonamide(602 mg, 80%): mp 122-124° C.; ¹H NMR (DMSO-d₆) δ 7.90 and 7.88 (2d,J=8.4, 8.3 Hz 1H), 7.68 (t, J_(HF)=52.8 Hz, 1H), 7.43-7.35 (m, 1H), 6.95(d, J=8.1 Hz, 1H), 4.75-4.68 and 4.59-4.56 (2m, 2H), 4.46 (q, J=5.0 Hz,1H), 3.98 (s, 3H), 3.80 (m, 4H), 3.69 (m, 4H), 3.64-3.24 (m, 5H),3.16-3.07 (m, 1H), 2.99-2.79 (m, 1H), 2.97 and 2.96 (2s, 3H), 1.93-1.54(m, 6H); Anal. Calcd. for C₂₅H₃₄F₂N₈O₅S.0.4 H₂O: C, 49.7; H, 5.8; N,18.6. Found: C, 49.7; H, 6.0; N, 18.6%.

To a solution of the above alcohol (326 mg, 0.55 mmol) and Et₃N (0.3 mL,2 mmol) in CH₂Cl₂ (10 mL) at 0° C. was added methanesulfonyl chloride(0.08 mL, 2 eq.). The mixture was stirred for additional 1 hr, with thetemperature being allowed to rise to room temperature. A solution of 40%aqueous dimethylamine (5 mL, excess) was added and the resulting mixturewas stirred for 20 hrs before the CH₂Cl₂ was removed under vacuum. Theresidue was diluted with water, and the resulting precipitate wascollected by filtration, washed with water, and dried. Chromatography onsilica, eluting first with CH₂Cl₂/EtOAc (4:1) and then with CH₂Cl₂/MeOH(94:6) gave 281 mg (82% yield) ofN-{(3S)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]piperidinyl}-N-[3-(dimethylamino)propyl]methanesulfonamide.

Hydrochloride: mp (MeOH/EtOAc) 213-216° C.; ¹H NMR (DMSO-d₆) δ 9.93 (brs, 1H), 7.94 and 7.88 (2d, J=8.4, 8.3 Hz, 1H), 7.69 (t, J_(HF)=52.9 Hz,1H), 7.43-7.36 (m, 1H), 6.95 (dd, J=8.1, 2.3 Hz, 1H), 4.76-7.58 (m, 2H),3.98 (s, 3H), 3.80 (m, 4H), 3.69 (m, 4H), 3.58 (br, 1H), 3.20-2.81 (m,6H), 3.02 and 3.00 (2s, 3H), 2.77 and 2.73 (2s, 6H), 1.95-1.85 (m, 5H),1.57 (m, 1H); Anal. Calcd. for C₂₇H₄₀ClF₂N₉O₄S H₂O: C, 47.8; H, 6.2; C,5.2, N, 18.6. Found: C, 47.8; H, 6.3; Cl, 5.2; N, 18.6%.

Example 64 Synthesis ofN-[2-({4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)ethyl]-N,N-diethylamine

A mixture of2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(vinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole(Example 3) (150 mg, 0.280 mmol) and N,N-diethylamine (0.14 mL, 1.35mmol) in THF (20 mL) was stirred at room temperature for 17 hrs,refluxed for 1 hr, and then stirred at room temperature for 4 hrs.1,4-Dioxane (20 mL) was added and the mixture was refluxed for 21 hrs.Additional N,N-diethylamine (0.14 mL, 1.35 mmol) was then added and themixture was refluxed for another 4.5 hrs. The reaction mixture wascooled to room temperature and the solvents were removed under vacuum.The residue was diluted with water and extracted with CH₂Cl₂ (2×). Theorganic layers were combined, dried (Na₂SO₄), and concentrated undervacuum. Chromatography on silica, eluting with CH₂Cl₂/MeOH (100:0 to98:2), gaveN-[2-({4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)ethyl]-N,N-diethylamine(54 mg, 53%).

Treatment with methanesulfonic acid in CH₂Cl₂/MeOH and recrystallizationfrom EtOAc/hexanes gave a methanesulfonate salt: mp 148-151° C.; ¹H NMR(DMSO-d₆) δ 9.32 (br s, 1H), 7.89 (d, J=8.1 Hz, 1H), 7.70 (t,J_(HF)=52.9 Hz, 1H), 7.41 (t, J=8.2 Hz, 1H), 6.96 (d, J=7.8 Hz, 1H),3.98 (s, 3H), 3.96 (m, 4H), 3.83 (m, 4H), 3.70 (br s, 4H), 3.59 (dd,J=10.0, 5.5 Hz, 2H), 3.44 (m, 2H), 3.36 (br s, 4H), 3.19 (m, 4H), 2.31(s, 3H), 1.19 (t, J=7.2 Hz, 6H); Anal. Calcd. for C₂₇H₄₁F₂N₉O₇S₂.0.4H₂O: C, 45.5; H, 5.9; N, 17.7. Found: C, 45.5; H, 5.9; N, 17.6%.

Example 65 Synthesis of2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[2-(1-piperidinyl)ethyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole

A mixture of2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(vinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole(Example 3) (150 mg, 0.280 mmol) and piperidine (0.14 mL, 1.42 mmol) inTHF (20 mL) was stirred at room temperature for 4 hrs. 1,4-Dioxane (20mL) was added and the mixture was refluxed for 18 hrs. After cooled toroom temperature, the solvents were removed under vacuum. The residuewas partitioned between CH₂Cl₂ and H₂O. The layers were separated andthe aqueous phase extracted with CH₂Cl₂ (1×). The combined organicextracts were dried (Na₂SO₄) and the solvent removed under vacuum.Chromatography on silica, eluting with CH₂Cl₂/MeOH (100:0 to 98:2) gave2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[2-(1-piperidinyl)ethyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole(147 mg, 84%).

Treatment with methanesulfonic acid in CH₂Cl₂/MeOH and recrystallizationfrom MeOH/EtOAc gave a methanesulfonate salt: mp 250-252° C.; ¹H NMR(DMSO-d₆) δ 9.21 (br s, 1H), 7.89 (d, J=7.9, 1H), 7.70 (t, J_(HF)=52.9Hz, 1H), 7.41 (t, J=8.2 Hz, 1H), 6.96 (d, J=7.8, 1H), 3.98 (s, 3H), 3.96(m, 4H), 3.83 (m, 4H), 3.70 (br s, 4H), 3.59 (m, 2H), 3.47 (m, 4H), 3.35(m, 4H), 2.93 (m, 2H), 2.31 (s, 3H), 1.83 (m, 2H), 1.70-1.54 (m, 3H),1.34 (m, 1H); Anal. Calcd. for C₂₈H₄₁F₂N₉O₇S₂: C, 46.85; H, 5.8; N,17.6. Found: C, 46.85; H, 5.9; N, 17.3%.

Example 66 Synthesis of2-(difluoromethyl)-4-methoxy-1-[4-(4-{[2-(4-methyl-1-piperazinyl)ethyl]sulfonyl}-1-piperazinyl)-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole

A mixture of2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(vinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole(Example 3) (150 mg, 0.280 mmol) and 1-methylpiperazine (0.16 mL, 1.44mmol) in THF (20 mL) was refluxed for 5 hrs and then stirred at roomtemperature for 3 days. Additional 1-methylpiperazine (0.16 mL, 1.44mmol) and 1,4-dioxane (20 mL) were added and the reaction mixture wasrefluxed for 20 hrs. The mixture was cooled to room temperature and thesolvents were removed under vacuum. The residue was partitioned betweenCH₂Cl₂ and H₂O. The layers were separated and the aqueous layer wasextracted with CH₂Cl₂ (1×). The combined organic extracts were dried(Na₂SO₄) and the solvent was removed under vacuum. Chromatography onsilica eluting with CH₂Cl₂/MeOH (100:0 to 95:5) followed byrecrystallization from CH₂Cl₂/hexanes gave2-(difluoromethyl)-4-methoxy-1-[4-(4-{[2-(4-methyl-1-piperazinyl)ethyl]sulfonyl}-1-piperazinyl)-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole(116 mg, 65%).

Treatment with methanesulfonic acid in CH₂Cl₂/MeOH and recrystallizationfrom MeOH/EtOAc gave a dimethanesulfonate salt: mp 198-201° C.; ¹H NMR(DMSO-d₆) δ 9.52 (br s, 1H), 7.89 (d, J=8.1 Hz, 1H), 7.69 (t,J_(HF)=52.9 Hz, 1H), 7.41 (t, J=8.2 Hz, 1H), 6.96 (d, J=7.9 Hz, 1H),3.98 (s, 3H), 3.93 (m, 4H), 3.82 (m, 4H), 3.70 (br s, 4H), 3.44-3.18 (m,12H), 3.00 (m, 4H), 2.79 (s, 3H), 2.35 (s, 6H); Anal. Calcd. forC₂₉H₄₆F₂N₁₀O₁₀S₃: C, 42.0; H, 5.6; N, 16.9. Found: C, 42.3; H, 5.6; N,16.6%.

Example 67 Synthesis of2-{4-[2-({4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)ethyl]-1-piperazinyl}ethanol

A mixture of2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(vinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole(Example 3) (150 mg, 0.280 mmol) and N-(2-hydroxyethyl)piperazine (360mg, 2.77 mmol) in 1,4-dioxane (15 mL) was refluxed for 3 hrs. Thereaction mixture was then cooled to room temperature and the solvent wasremoved under vacuum. The residue was partitioned between CH₂Cl₂ andH₂O. The phases were separated, the organic phase was dried (Na₂SO₄),and the solvent was removed under vacuum. Recrystallization fromCH₂Cl₂/hexanes gave2-{4-[2-({4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)ethyl]-1-piperazinyl}ethanol(134 mg, 72%).

Treatment with methanesulfonic acid in CH₂Cl₂/MeOH and recrystallizationfrom MeOH/EtOAc gave a dimethanesulfonate salt: mp 236-238° C.; ¹H NMR(DMSO-d₆) δ 9.46 (br s, 1H), 7.89 (d, J=8.1 Hz, 1H), 7.69 (t,J_(HF)=52.9 Hz, 1H), 7.41 (t, J=8.2 Hz, 1H), 6.96 (d, J=7.9 Hz, 1H),3.98 (s, 3H), 3.93 (m, 4H), 3.82 (m, 4H), 3.71 (m 4H), 3.70-3.66 (m,4H), 3.40-3.32 (m, 6H), 3.18 (t, J=4.9 Hz, 4H), 3.08-2.99 (m, 4H), 2.67(m, 2H), 2.34 (s, 6H); Anal. Calcd. for C₃₀H₄₈F₂N₁₀O₁₁S₃.1.5 H₂O: C,40.7; H, 5.8; N, 15.8. Found: C, 40.3; H, 5.6; N, 15.8%.

Example 68 Synthesis of 2-(difluoromethyl)-1-[4-(4-{[2-(1H-imidazol-1-yl)ethyl]sulfonyl}-1-piperazinyl)-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-methoxy-1H-benzimidazole

A mixture of2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(vinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole(Example 3) (150 mg, 0.280 mmol), imidazole (38 mg, 0.558 mmol), andpyridine (2 drops) in DMSO (5 mL) was heated at 135-140° C. for 5 days.The mixture was then poured over ice and extracted with CH₂Cl₂ (3×). Thecombined organic extracts were washed with H₂O (1×), dried (Na₂SO₄) andconcentrated. Chromatography on silica, eluting with CH₂Cl₂/MeOH (100:0to 95:5), followed by recrystallization from CH₂Cl₂/hexanes gave2-(difluoromethyl)-1-[4-(4-{[2-(1H-imidazol-1-yl)ethyl]sulfonyl}-1-piperazinyl)-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-methoxy-1H-benzimidazole(45 mg, 27%): mp 188-191° C.; ¹H NMR (CDCl₃) δ 7.84 (dd, J=8.4, 0.6 Hz,1H), 7.55 (s, 1H), 7.41 (t, J_(HF)=53.5 Hz, 1H), 7.35 (t, J=8.2 Hz, 1H),7.10 (t, J=1.0 Hz, 1H), 6.96 (t, J=1.3 Hz, 1H), 6.82 (d, J=7.7 Hz, 1H),4.46 (t, J=7.0 Hz, 2H), 4.05 (s, 3H), 3.94 (br s, 4H), 3.87 (br s, 4H),3.78 (m, 4H), 3.35 (t, J=7.1 Hz, 2H), 3.29 (br s, 4H); Anal. Calcd. forC₂₅H₃₀F₂N₁₀O₄S: C, 49.7; H, 5.0; N, 23.2. Found: C, 49.3; H, 4.9; N,23.2%.

Example 69 Synthesis of2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[2-(2-pyridinyl)ethyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole

DIPEA (0.29 mL, 1.66 mmol) was added to a suspension of2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole(Example 2) (150 mg, 0.336 mmol) and2-[2-(chlorosulfonyl)ethyl]pyridinium chloride (122 mg, 0.504 mmol) inCH₂Cl₂ (10 mL) at room temperature under nitrogen, and the mixture wasstirred for 4 hrs. Additional 2-[2-(chlorosulfonyl)ethyl]pyridiniumchloride (41 mg, 0.169 mmol) was added and the reaction mixture wasstirred for another 20 hrs. Water was added and the phases wereseparated. The aqueous phase was extracted with CH₂Cl₂, the combinedorganic extracts were dried (Na₂SO₄), and the solvent was removed undervacuum. Chromatography on silica, eluting with CH₂Cl₂/MeOH (100:0 to98.5:1.5), gave2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[2-(2-pyridinyl)ethyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole(148 mg, 71%).

Treatment with methanesulfonic acid in CH₂Cl₂/MeOH and recrystallizationfrom MeOH/EtOAc gave a methanesulfonate salt: mp 154-157° C.; ¹H NMR(DMSO-d₆) δ 8.64 (d, J=4.8 Hz, 1H), 8.07 (t, J=6.9 Hz, 1H), 7.88 (d,J=8.0 Hz, 1H), 7.69 (t, J_(HF)=52.9 Hz, 1H), 7.67-7.52 (m, 2H), 7.41 (t,J=8.2 Hz, 1H), 6.96 (d, J=7.8 Hz, 1H), 3.98 (s, 3H), 3.91 (m, 4H), 3.82(m, 4H), 3.70 (br s, 4H), 3.59 (dd, J=9.0, 6.7 Hz, 2H), 3.30-3.27 (m,6H), 2.31 (s, 3H); Anal. Calcd. for C₂₈H₃₅F₂N₉O₇S₂.0.7 H₂O: C, 46.4; H,5.1; N, 17.4. Found: C, 46.4; H, 5.2; N, 17.6%.

Example 70 Synthesis of2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[2-(4-pyridinyl)ethyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole

DIPEA (0.29 mL, 1.66 mmol) was added to a suspension of2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole(Example 2) (150 mg, 0.336 mmol) and4-[2-(chlorosulfonyl)ethyl]pyridinium chloride (122 mg, 0.504 mmol) inCH₂Cl₂ (10 mL) at room temperature under nitrogen, and the mixture wasstirred for 3 hrs. Additional 4-[2-(chlorosulfonyl)ethyl]pyridiniumchloride (41 mg, 0.169 mmol) was added and the mixture stirred foranother 21 hrs. Water was added and the phases were separated. Theaqueous phase was extracted with CH₂Cl₂ (1×), the combined organicextracts were dried (Na₂SO₄), and the solvent was removed under vacuum.Chromatography on silica eluting with CH₂Cl₂/MeOH (100:0 to 98:2)followed by recrystallization from CH₂Cl₂/MeOH gave2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[2-(4-pyridinyl)ethyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole(134 mg, 65%).

Treatment with methanesulfonic acid in CH₂Cl₂/MeOH and recrystallizationfrom MeOH/EtOAc gave a methanesulfonate salt: mp 290-293° C.; ¹H NMR(DMSO-d₆) δ 8.76 (dd, J=5.4, 1.1 Hz, 2H), 7.89-7.87 (m, 3H), 7.69 (t,J_(HF)=52.9 Hz, 1H), 7.41 (t, J=8.2 Hz, 1H), 6.96 (d, J=7.8 Hz, 1H),3.98 (s, 3H), 3.93 (m, 4H), 3.82 (m, 4H), 3.70 (br s, 4H), 3.59 (dd,J=8.8, 6.8 Hz, 2H), 3.30-3.23 (m, 6H), 2.31 (s, 3H); Anal. Calcd. forC₂₈H₃₅F₂N₉O₇S₂: C, 47.25; H, 5.0; N, 17.7. Found: C, 47.1; H, 5.0; N,17.6%.

Example 71 Synthesis of2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(3-pyridinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole

DIPEA (0.78 mL, 4.48 mmol) was added to a mixture of2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole(Example 2) (200 mg, 0.449 mmol) and 3-pyridinesulfonyl chloride (159mg, 0.859 mmol) at room temperature under nitrogen. The reaction mixturewas stirred at room temperature for 18.5 hrs. Water was added and thephases were separated. The organic phase was dried (Na₂SO₄) and thesolvent was removed under vacuum. Chromatography on silica, eluting withCH₂Cl₂/MeOH (99:1), gave2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(3-pyridinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole(227 mg, 86%).

Treatment with methanesulfonic acid in CH₂Cl₂/MeOH and recrystallizationfrom MeOH/EtOAc gave a methanesulfonate salt: mp 243-246° C.; ¹H NMR(DMSO-d₆) δ 8.94 (dd, J=2.2, 0.5 Hz, 1H), 8.88 (dd, J=4.8, 1.6 Hz, 1H),8.19 (ddd, J=8.1, 2.3, 1.7 Hz, 1H), 7.84 (dd, J=8.4, 0.4 Hz, 1H), 7.68(ddd, J=8.1, 4.8, 0.7 Hz, 1H), 7.63 (t, J_(HF)=52.8 Hz, 1H), 7.39 (t,J=8.2 Hz, 1H), 6.94 (d, J=7.8 Hz, 1H), 3.96 (s, 3H), 3.93 (m, 4H), 3.77(m, 4H), 3.66 (br s, 4H), 3.11 (br s, 4H), 2.33 (s, 3H); Anal. Calcd,for C₂₆H₃₁F₂N₉O₇S₂: C, 45.7; H, 4.6; N, 18.4. Found: C, 45.6; H, 4.6; N,18.3%.

Example 72 Synthesis ofN-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}-2-(dimethylamino)ethanesulfonamide

Reaction of1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinamine(Example 17) with 2-chloroethanesulfonyl chloride, as in previousexamples, gaveN-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}ethylenesulfonamidein 42% yield: mp (CH₂Cl₂/MeOH) 221-224° C.; ¹H NMR (DMSO-d₆) δ 7.87 (dd,J=7.9, 0.6 Hz, 1H), 7.68 (t, J_(HF)=52.9 Hz, 1H), 7.45 (br s, 1H), 7.41(t, J=8.2 Hz, 1H), 6.95 (d, J=7.8 Hz, 1H), 6.79 (dd, J=16.5, 9.9 Hz,1H), 6.07 (d, J=16.5 Hz, 1H), 5.96 (d, J=9.9 Hz, 1H), 4.46 (t, J=17.0Hz, 1H), 9.98 (s, 3H), 3.81-3.78 (m, 4H), 3.70-3.69 (m, 4H), 3.41-3.32(m, 4H), 1.92 (br s, 2H), 1.44-1.42 (m, 2H); Anal. Calcd. forC₂₃H₂₈F₂N₈O₄S: C, 50.2; H, 5.1; N, 20.3. Found: C, 50.3; H, 5.1; N,20.5%.

Reaction of the above vinylsulfonamide with 40% aqueous dimethylaminegaveN-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}-2-(dimethylamino)ethanesulfonamidein 65% yield: Hydrochloride: mp (MeOH) 236-239° C.; ¹H NMR (DMSO-d₆) δ10.31 (br s, 1H), 7.88 (dd, J=8.4, 0.4 Hz, 1H), 7.69 (t, J_(HF)=52.9 Hz,1H), 7.65 (d, J=7.5 Hz, 1H), 7.41 (t, J=8.2 Hz, 1H), 6.95 (d, J=7.8 Hz,1H), 4.52 (t, J=16.8 Hz, 2H), 3.98 (s, 3H), 3.82-3.79 (m, 4H), 3.71-3.69(m, 4H), 3.62-3.49 (m, 3H), 3.40-3.36 (m, 2H), 3.25-3.24 (m, 2H), 2.81(s, 6H), 2.00 (br, 2H), 1.50-1.45 (m, 2H); Anal. Calcd. forC₂₁H₃₆ClF₂N₉O₄S: C, 47.5; H, 5.7; N. 19.9; Cl, 5.6. Found: C, 47.6; H,5.8; N, 20.1; Cl, 5.9%.

Example 73 Synthesis ofN-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}-2-(dimethylamino)-N-methylethanesulfonamide

Reaction of1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole(Example 2) and tert-butyl methyl(4-piperidinyl)carbamate as in previousexamples gave tert-butyl1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl(methyl)carbamatein 93% yield: mp (CH₂Cl₂/MeOH) 182-184° C.; ¹H NMR (DMSO-d₆) δ 7.89 (d,J=7.9 Hz, 1H), 7.69 (t, J_(HF)=52.9 Hz, 1H), 7.41 (t, J=8.2 Hz, 1H),6.95 (d, J=7.8 Hz, 1H), 4.83-4.72 (m, 2H), 4.09 (br, 1H), 3.98 (s, 3H),3.81-3.79 (m, 4H), 3.70-3.69 (m, 4H), 3.07-2.93 (m, 2H), 2.66 (s, 3H),1.66 (m, 4H), 1.41 (s, 9H); Anal. Calcd. for C₂₇H₃₆F₂N₈O₄: C, 56.4; H,6.3; N, 19.7. Found: C, 56.6; H, 6.3; N, 19.8%.

Deprotection of the above carbamate with TFA in CH₂Cl₂ gave1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N-methyl-4-piperidinaminein 96% yield: ¹H NMR (DMSO-d₆) δ 7.89 (dd, J=8.3, 0.5 Hz, 1H), 7.68 (t,J_(HF)=52.9 Hz, 1H), 7.40 (t, J=8.2 Hz, 1H), 6.94 (d, J=7.7 Hz, 1H),4.42 (t, J=14.2 Hz, 1H), 3.98 (s, 3H), 3.80-3.78 (m, 4H), 3.70-3.69 (m,4H), 3.36-3.18 (m, 2H), 2.62-2.54 (m, 1H), 2.30 (s, 3H), 1.89 (br, 2H),1.64 (br, 1H), 1.24 (br, 2H).

Reaction of the above amine with chloroethanesulfonyl chloride gaveN-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}-N-methylethylenesulfonamidein 65% yield: mp (CH₂Cl₂/MeOH) 223-225° C.; ¹H NMR (DMSO-d₆) δ 7.88 (d,J=8.0 Hz, 1H), 7.68 (t, J_(HF)=52.9 Hz, 1H), 7.41 (t, J=8.2 Hz, 1H),6.95 (d, J=7.9 Hz, 1H), 6.85 (dd, J=16.4, 10.0 Hz, 1H), 6.07 (dd,J=15.2, 13.2 Hz, 2H), 4.82-4.70 (m, 2H), 3.98 (s, 3H), 3.95-3.88 (m,1H), 3.81-3.79 (m, 4H), 3.70-3.69 (m, 4H), 3.10-2.97 (m, 2H), 2.62 (s,3H), 1.72 (m, 4H); Anal. Calcd. for C₂₄H₃₀F₂N₈O₄S: C, 51.1; H, 5.4; N,19.9. Found: C, 50.8; H, 5.3; N, 19.9%.

Reaction of the above vinylsulfonamide with 40% aqueous dimethylaminegaveN-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}-2-(dimethylamino)-N-methylethanesulfonamidein 86% yield.

Hydrochloride: mp (MeOH) 242-245° C.; ¹H NMR (DMSO-d₆) δ 10.47 (br, 1H,N⁺H), 7.89 (d, J=8.0 Hz, 1H), 7.69 (t, J_(HF)=52.9 Hz, 1H), 7.41 (t,J=8.2 Hz, 1H), 6.95 (d, J=7.8 Hz, 1H), 4.84-4.74 (m, 2H), 3.98 (s, 3H),3.98-3.91 (m, 1H), 3.82-3.80 (m, 4H), 3.70-3.63 (m, 6H), 3.40-3.36 (m,2H), 3.14-3.00 (m, 2H), 2.81 (s. 6H), 2.75 (s, 3H), 1.78 (m, 4H); Anal.Calcd. for C₂₆H₃₈ClF₂N₉O₄S 0.25 H₂O: C, 48.0; H, 6.0; Cl, 5.5; N, 19.4.Found: C, 48.0; H, 6.1; Cl. 5.7; N, 19.5%.

Example 74 Synthesis ofN-{4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]phenyl}-2-(dimethylamino)ethanesulfonamide

A mixture of1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole(Example 2), 4-[(tert-butoxycarbonyl)amino]phenylboronic acid (90 mg,0.380 mmol), PdCl₂(dppf) (10.3 mg, 0.0126 mmol) and aq. K₂CO₃ (2M, 2 mL)in 1,4-dioxane (10 mL) was refluxed under nitrogen for 1 hr. The mixturewas cooled to room temperature and diluted with H₂O, and the aqueousphase was extracted with CH₂Cl₂ (3×). The combined organic extracts weredried (Na₂SO₄) and the solvent was removed under vacuum. Chromatographyon alumina, eluting with CH₂Cl₂, followed by recrystallization fromCH₂Cl₂/MeOH/hexanes gave tert-butyl4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]phenylcarbamate(99 mg, 71%): mp (CH₂Cl₂/MeOH/hexanes) 188-190° C.; ¹H NMR (CDCl₃) δ8.41 (d, J=8.8 Hz, 2H), 8.08 (dd, J=8.4, 0.6 Hz, 1H), 7.62 (t,J_(HF)=53.4 Hz, 1H), 7.52 (d, J=8.8 Hz, 2H), 7.41 (t, J=8.2 Hz, 1H),6.86 (d, J=7.7 Hz, 1H), 6.69 (s, 1H), 4.12 (m, 2H), 4.07 (s, 3H), 3.99(m, 2H), 3.85 (m, 4H), 1.55 (s, 9H); Anal. Calcd. for C₂₇H₂₉F₂N₇O₄: C,58.6; H, 5.3; N, 17.2. Found: C, 58.5; H, 5.0; N, 17.7%.

Reaction of the above carbamate (300 mg, 0.542 mmol) with an excess ofTFA (2 mL) in CH₂Cl₂ (10 mL) at room temperature for 3 hrs, followed bytreatment with aq. NH₃ gave4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]aniline(217 mg, 88%), which was used in the next step without furtherpurification: ¹H NMR (DMSO-d₆) δ 8.17 (d, J=8.7 Hz, 2H), 8.05 (dd,J=8.3, 0.4 Hz, 1H), 7.80 (t, J_(HF)=52.9 Hz, 1H), 7.47 (t, J=8.2 Hz,1H), 6.99 (d, J=7.8 Hz, 1H), 6.68 (d, J=8.8 Hz, 2H), 6.05 (s, 2H), 4.01(br s, 2H), 3.99 (s, 3H), 3.88 (br s, 2H), 3.75 (m, 4H).

2-Chloroethanesulfonyl chloride (0.090 mL, 0.861 mmol) was addeddrop-wise to a suspension of the above amine (190 mg, 0.419 mmol) inpyridine (4 mL) at 0° C. The mixture was stirred at 0° C. for 2.5 hrs,then diluted with H₂O, and warmed to room temperature. The resultingprecipitate was collected by filtration and dried to giveN-{4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]phenyl}ethylenesulfonamide,which was used in the next step without further purification.

Excess dimethylamine (2 mL; 40% solution in H₂O) was added to asuspension of the above vinylsulfonamide in THF (10 mL) at roomtemperature. The mixture was stirred at room temperature for 21 hrs andthen at reflux for 2 hrs. After cooled to room temperature, the solventwas removed under vacuum. The residue was partitioned between H₂O andCH₂Cl₂. The aqueous layer was extracted with CH₂Cl₂ (1×), the combinedorganic extracts were dried (Na₂SO₄), and the solvent was removed undervacuum. Chromatography on silica, eluting with CH₂Cl₂/MeOH (100:0 to95:5), gaveN-{4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]phenyl}-2-(dimethylamino)ethanesulfonamide(169 mg, 68% over 2 steps).

Treatment with methanesulfonic acid in CH₂Cl₂/MeOH and recrystallizationfrom MeOH/EtOAc gave a methanesulfonate salt: mp (MeOH/EtOAc) 218-220°C.; ¹H NMR (DMSO-d₆) δ 10.68 (br s, 1H), 9.47 (br s, 1H), 8.45 (d, J=8.8Hz, 2H), 8.07 (d, J=8.1 Hz, 1H), 7.82 (t, J_(HF)=52.8 Hz, 1H), 7.49 (t,J=8.2 Hz, 1H), 7.43 (d, J=8.9 Hz, 2H), 7.01 (d, J=7.9 Hz, 1H), 4.06 (m,2H), 4.00 (s, 3H), 3.92 (m, 2H), 3.79-3.74 (m, 6H), 3.50 (dd, J=9.4, 6.3Hz, 2H), 2.82 (s, 6H), 2.31 (s, 3H); Anal. Calcd. for C₂₇H₃₄F₂N₈O₇S₂: C,47.4; H, 5.0; N, 16.4. Found: 47.1; H, 5.1; N, 16.2%.

Example 75 Synthesis ofN-{4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]phenyl}-2-(dimethylamino)-N-methylethanesulfonamide

NaH (95%, 11 mg, 0.435 mmol) was added to a suspension of tert-butyl4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]phenylcarbamate(Example 74) (120 mg, 0.217 mmol) in DMF (3 mL) at 0° C. After stirringat 0° C. for 15 min, iodomethane (0.020 mL, 0.321 mmol) was added. Thereaction mixture was warmed to room temperature, stirred for additional17 hrs, and then diluted with H₂O. The resulting precipitate wascollected by filtration and dried to give tert-butyl4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]phenyl(methyl)carbamate(104 mg, 85%): mp (CH₂Cl₂/MeOH) 205-208° C.; ¹H NMR (CDCl₃) δ 8.42 (d,J=8.8 Hz, 2H), 8.09 (dd, J=8.4, 0.6 Hz, 1H), 7.63 (t, J_(HF)=53.5 Hz,1H), 7.45-7.40 (m, 3H), 6.86 (d, J=7.8 Hz, 1H), 4.13 (m, 2H), 4.07 (s,3H), 4.00 (m, 2H), 3.86 (m, 4H), 3.35 (s, 3H), 1.50 (s, 9H); Anal.Calcd. for C₂₈H₃₁F₂N₇O₄: C, 59.25; H, 5.5; N, 17.3. Found: C, 59.0; H,5.3; N, 17.2%.

Reaction of the above carbamate (235 mg, 0.414 mmol) with an excess ofTFA (1.2 mL) in CH₂Cl₂ (6 mL) at room temperature for 2 hrs, followed bytreatment with aq. NH₃ gave4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N-methylaniline(168 mg, 87%): ¹H NMR (DMSO-d₆) δ 8.23 (d, J=8.9 Hz, 2H), 8.06 (d, J=8.0Hz, 1H), 7.80 (t, J_(HF)=52.9 Hz, 1H), 7.47 (t, J=8.2 Hz, 1H), 6.99 (d,J=7.8 Hz, 1H), 6.67 (d, J=8.9 Hz, 2H), 6.63 (q, J=4.8 Hz, 1H), 4.01 (brs, 2H), 3.99 (s, 3H), 3.88 (br s, 2H), 3.76 (t, J=4.8 Hz, 4H), 2.79 (d,J=4.9 Hz, 3H).

2-Chloroethanesulfonyl chloride (0.060 mL, 0.574 mmol) was addeddropwise to a mixture of the above amine (160 mg, 0.342 mmol) and DIPEA(0.18 mL, 1.03 mmol) in CH₂Cl₂ (20 mL) at 0° C. The mixture was stirredat 0° C. for 3.5 hrs, when additional DIPEA (0.18 mL, 1.03 mmol) and2-chloroethanesulfonyl chloride (0.030 mL, 0.287 mmol) were added. Themixture was stirred for another 2 hrs at 0° C. The reaction mixture wasthen quenched with H₂O and the organic layer was washed successivelywith HOAc (1%) and aq. NH₃. The aqueous layer was extracted with CH₂Cl₂(5×), the combined organic extracts were dried (Na₂SO₄), and the solventwas removed under vacuum to giveN-{4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]phenyl}-N-methylethylenesulfonamidewhich was used in the next step without further purification.

Excess dimethylamine (1.0 mL, 40% solution in H₂O) was added to asolution of the above vinylsulfonamide in THF (10 mL) at roomtemperature and the mixture was stirred for 3 days. The solvent wasremoved under vacuum and the residue was partitioned between H₂O andCH₂Cl₂. The aqueous phase was extracted with CH₂Cl₂ (2×), the combinedorganic extracts were dried (Na₂SO₄), and the solvent was removed undervacuum. Chromatography on silica, eluting with CH₂Cl₂/MeOH (100:0 to98:2), followed by recrystallization from CH₂Cl₂/MeOH/hexanes, gaveN-{4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]phenyl}-2-(dimethylamino)-N-methylethanesulfonamide(104 mg, 50% yield over 2 steps).

Treatment with methanesulfonic acid in CH₂Cl₂/MeOH and recrystallizationfrom MeOH/EtOAc gave a methanesulfonate salt: mp (MeOH/EtOAc) 218-220°C.; ¹H NMR (DMSO-d₆) δ 9.45 (br s, 1H), 8.50 (d, J=8.8 Hz, 2H), 8.07 (d,J=7.9 Hz, 1H), 7.83 (t, J_(HF)=52.8 Hz, 1H), 7.68 (d, J=8.8 Hz, 2H),7.49 (t, J=8.2 Hz, 1H), 7.02 (d, J=7.9 Hz, 1H), 4.08 (m, 2H), 4.00 (s,3H), 3.94 (m, 2H), 3.79 (m, 4H), 3.72 (dd, J=9.7, 6.2 Hz, 2H), 3.47 (m,2H), 3.41 (s, 3H), 2.82 (s, 6H), 2.30 (s, 3H); Anal. Calcd. forC₂₈H₃₆F₂N₈O₇S₂.0.35 H₂O: C, 47.7; H, 5.25; N, 15.9. Found: C, 47.7; H,4.9; N, 15.8%.

Example 76 Synthesis ofN-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-azetidinyl}-2-(dimethylamino)ethanesulfonamide

Reaction of1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-azetidinamine(Example 30) with 2-chloroethanesulfonyl chloride as in previousexamples gaveN-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-azetidinyl}ethylenesulfonamidein 9.7% yield: mp (CH₂Cl₂/MeOH) 250-252° C.; ¹H NMR (DMSO-d₆) δ 8.20(br, 1H), 7.96 (dd, J=7.9, 0.6 Hz, 1H), 7.72 (t, J_(HF)=53.0 Hz, 1H),7.40 (t, J=8.2 Hz, 1H), 6.95 (d, J=7.8 Hz, 1H), 6.82 (dd, J=16.5, 10.0Hz, 1H), 6.08 (dd, J=26.8, 13.2 Hz, 2H), 4.47 (t, J=7.6 Hz, 1H), 4.37(t, J=8.1 Hz, 1H), 4.26-4.20 (m, 1H), 4.04-3.97 (m, 2H), 3.97 (s, 3H),3.80-3.77 (m, 4H), 3.68 (m, 4H); Anal. Calcd. for C₂₁H₂₄F₂N₈O₄S; C,48.3; H, 4.6; N, 21.4. Found: C, 48.4; H, 4.7; N, 21.6%.

Reaction of the above vinylsulfonamide with 40% aqueous dimethylaminegaveN-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-azetidinyl}-2-(dimethylamino)ethanesulfonamidein 74% yield.

Hydrochloride: mp (MeOH) 214-216C°; ¹H NMR (DMSO-d₆) δ 10.25 (br s, 1H,exchangeable with D₂O), 8.45 (d, J=7.40 Hz, 1H), 7.98 (d, J=8.41 Hz,1H), 7.74 (t, J_(HF)=53.0 Hz, 1H), 7.40 (t, J=8.2 Hz, 1H), 6.95 (d,J=7.7 Hz, 1H), 4.55-4.36 (m, 3H), 4.15-4.00 (m, 2H), 3.97 (s, 3H),3.97-3.98 (m, 4H), 3.69 (m, 4H), 3.62-3.59 (m, 2H), 3.41-3.38 (m, 2H),2.80 (s, 6H); Anal. Calcd. for C₂₃H₃₂ClF₂N₉O₄S.0.25 H₂O: C, 45.4; H,5.4; Cl, 6.2; N, 20.7. Found: C, 45.4; H, 5.2; Cl; 6.0; N, 20.8%.

Example 77 Synthesis ofN-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-azetidinyl}-2-(dimethylamino)-N-methylethanesulfonamide

Reaction of tert-butyl1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-azetidinylcarbamate(Example 30) with NaH/MeI in THF as in previous examples gave tert-butyl1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-azetidinyl(methyl)-carbamatein 95% yield: mp (CH₂Cl₂/MeOH) 186-188° C.; ¹H NMR (DMSO-d₆) δ 8.00 (d,J=8.3 Hz, 1H), 7.75 (t, J_(HF)=53.0 Hz, 1H), 7.39 (t, J=8.2 Hz, 1H),6.95 (d, J=8.0 Hz, 1H), 4.88 (br, 1H), 4.40-4.15 (m, 4H), 3.97 (s, 3H),3.80-3.78 (m, 4H), 3.69 (m, 4H), 2.89 (s, 3H), 1.41 (s, 9H); Anal.Calcd. for C₂₅H₃₂F₂N₈O₄: C, 54.9; H, 5.9; N, 20.5. Found: C, 55.1; H,5.9; N, 20.6%.

Deprotection of the above carbamate with TFA in CH₂Cl₂ as in previousexamples gave1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N-methyl-3-azetidinaminein 96% yield: mp (CH₂Cl₂/hexanes) 199-201° C.; ¹H NMR (DMSO-d₆) δ 7.99(dd, J=8.4, 0.5 Hz, 1H), 7.75 (t, J_(HF)=53.1 Hz, 1H), 7.40 (t, J=8.2Hz, 1H), 6.95 (d, J=7.8 Hz, 1H), 4.30-4.20 (m, 2H), 3.97 (s, 3H),3.89-3.85 (m, 1H), 3.80-3.77 (m, 5H), 3.70-3.68 (m, 4H), 3.64-3.58 (m,1H), 2.26 (s, 3H).

Reaction of the above amine with 2-chloroethanesulfonyl chloride as inprevious examples gaveN-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-azetidinyl}-N-methylethylenesulfonamidein 44% yield: mp (CH₂Cl₂/MeOH) 244-246° C.; ¹H NMR (DMSO-d₆) δ 7.98 (d,J=8.4 Hz, 1H), 7.74 (t, J_(HF)=53.0 Hz, 1H), 7.40 (t, J=8.2 Hz, 1H),6.95 (d, J=7.8 Hz, 1H), 6.86 (dd, J=16.5, 10.0 Hz, 1H), 6.17 (dd,J=13.2, 7.7 Hz, 2H), 4.74-4.67 (m, 1H), 4.22-4.20 (m, 4H), 3.98 (s, 3H),3.80-3.78 (m, 4H), 3.68 (m, 4H), 2.86 (s, 3H); Anal. Calcd. forC₂₂H₂₆F₂N₈O₄S: C, 49.3; H, 4.9; N, 20.9. Found: C, 49.3; H, 4.9; 20.9%.

Reaction of the above vinylsulfonamide with 40% aqueous dimethylaminegaveN-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-azetidinyl}-2-(dimethylamino)-N-methylethanesulfonamidein 88% yield.

Methanesulfonate: mp (CH₂Cl₂/MeOH/EtOAc) 239-242° C.; ¹H NMR (DMSO-d₆) δ9.44 (br, 1H, exchangeable with D₂O), 7.99 (dd, J=8.4, 0.5 Hz, 1H), 7.75(t, J_(HF)=53.0 Hz, 1H), 7.40 (t, J=8.2 Hz, 1H), 6.96 (d, J=7.7 Hz, 1H),4.88-4.81 (m, 1H), 4.49-4.29 (m, 4H), 3.98 (s, 3H), 3.82-3.79 (m, 4H),3.69 (m, 4H), 3.60-3.56 (m, 2H), 3.46-3.43 (m, 2H), 3.01 (s, 3H), 2.86(s, 6H), 2.30 (s, 3H); Anal. Calcd. for C₂₅H₃₇F₂N₉O₇S₂.0.75 H₂O: C,43.4; H, 5.6; N, 18.2. Found: C, 43.4; H, 5.5; N, 17.9%.

Example 78 Synthesis oftrans-N-(4-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}cyclohexyl)methanesulfonamide

Reaction of1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole(Example 2) with tert-butyl trans-4-aminocyclohexylcarbamate as inprevious examples gave tert-butyltrans-4-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}cyclohexylcarbamatein 88% yield: mp (CH₂Cl₂/hexanes) 218-221° C.; ¹H NMR (DMSO-d₆) δ 8.10and 7.97 (2d, J=8.3, 8.1 Hz, 1H), 7.87 and 7.72 (2t, J_(HF)=53.1, 53.0Hz, 1H) 7.83 and 7.77 (2d, J=7.7, 8.10 Hz, 1H), 7.38 (q, J=8.3 Hz, 1H),6.94 (t, J=8.0 Hz, 1H), 6.75-6.70 (m, 1H), 3.98 and 3.97 (2s, 3H), 3.97(m, 4H), 3.71-3.69 (m, 4H), 1.98-1.91 (m, 2H), 1.85-1.82 (m, 2H),1.40-1.22 (m, 4H), 1.38 (s, 9H); Anal. Calcd. for C₂₇H₃₆F₂N₈O₄: C, 56.4;H, 6.3; N, 19.5. Found: C, 56.6; H, 6.5; N, 19.3%.

Deprotection of the above carbamate with TFA in CH₂Cl₂ as in previousexamples gavetrans-N¹-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1,4-cyclohexanediaminein 100% yield: mp (CH₂Cl₂/hexanes) 220-222° C.; ¹H NMR (DMSO-d₆) δ 8.10and 7.98 (2d, J=7.9, 8.1 Hz, 1H), 7.88 and 7.73 (t, J_(HF)=53.2 Hz, 1H),7.81 and 7.74 (2d, J=7.9, 9.8 Hz, 1H), 7.42-7.35 (m, 1H), 6.94 (t, J=7.6Hz, 1H), 3.98 and 3.97 (2s, 3H), 3.78-3.77 (m, 4H), 3.74-3.72 (m, 1H),3.71-3.69 (m, 4H), 2.55-2.53 (m, 1H), 1.93-1.87 (m, 2H), 1.83-1.76 (m,2H), 1.40-1.28 (m, 2H), 1.19-1.09 (m, 2H).

Reaction of the above amine with methanesulfonyl chloride as in previousexamples gavetrans-N-(4-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}cyclohexyl)methanesulfonamidein 90% yield: mp (CH₂Cl₂/MeOH) 269-272° C.; ¹H NMR (DMSO-d₆) δ 8.10 and7.97 (d, J=8.3 Hz, 1H), 7.88 and 7.73 (2t, J_(HF)=53.2, 53.9 Hz, 1H)7.86 and 7.80 (d, J=7.6, 8.0 Hz, 1H), 7.38 (q, J=8.1 Hz, 1H), 7.02-6.92(m, 2H), 3.98 and 3.97 (2s, 3H), 3.77-3.69 (m, 9H), 3.13 (br, 1H), 2.93and 2.92 (2s, 3H), 1.98-1.96 (m, 4H), 1.42-1.32 (m, 4H); Anal. Calcd.for C₂₃H₃₀F₂N₈O₄S: C, 50.0; H, 5.5; N, 20.3. Found: C, 50.0; H, 5.4; N,20.5%.

Example 79 Synthesis ofcis-N-(4-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}cyclohexyl)methanesulfonamide

Similar to the previous Example, coupling of1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole(Example 2) and tert-butyl cis-4-aminocyclohexylcarbamate gavetert-butylcis-4-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}-cyclohexylcarbamatein 90% yield: mp (CH₂Cl₂/hexanes) 192-195° C.; ¹H NMR (DMSO-d₆) δ 8.13and 7.97 (2d, J=8.1, 8.3 Hz, 1H), 7.94 and 7.72 (2t, J_(HF)=53.1 Hz,1H), 7.71 and 7.64 (2d, J=6.8, 7.1 Hz, 1H), 7.39 (q, J=8.3 Hz, 1H), 6.94(dd, J=8.0, 2.4 Hz, 1H), 3.97 (s, 3H), 3.88 (br, 1H), 3.78-3.77 (m, 4H),3.70-3.69 (m, 4H), 3.46-3.39 (m, 1H), 1.80-1.55 (m, 8H), 1.39 (s, 9H):Anal. Calcd. for C₂₇H₃₆F₂N₈O₄: C, 56.4; H, 6.3; N, 19.5. Found: C, 56.6;H, 6.5; N, 19.7%.

Deprotection of the above carbamate with TFA in CH₂Cl₂ as in previousexamples gavecis-N¹-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1,4-cyclohexanediaminein 99% yield: mp (CH₂Cl₂/hexanes) 171-173° C.; ¹H NMR (DMSO-d₆) δ 8.13and 7.98 (2d, J=8.0, 8.3 Hz, 1H), 7.95 and 7.73 (2t, J_(HF)=53.1 Hz,1H), 7.76 and 7.69 (2d, J=7.4, 7.6 Hz, 1H), 7.41-7.36 (m, 1H), 6.94 (dd,J=8.1, 1.7 Hz, 1H), 3.97 (s, 3H), 3.92-3.85 (m, 1H), 3.78-3.77 (m, 4H),3.69 (m, 4H), 2.93-2.85 (m, 1H), 1.85-1.72 (m, 2H), 1.62-1.49 (m, 7H).

Reaction of the above amine with methanesulfonyl chloride as in previousexamples gavecis-N-(4-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}cyclohexyl)methanesulfonamidein 88% yield: ¹H NMR (DMSO-d₆) δ 8.13 and 7.97 (2d, J=8.3 Hz, 1H), 7.94and 7.73 (2 t, J_(HF)=53.3, 53.1 Hz, 1H), 7.81 and 7.77 (2d, J=6.5, 7.3Hz, 1H), 7.42-7.36 (m, 1H), 6.96-6.89 (m, 2H), 3.97 (s, 3H), 3.88-3.86(m, 1H), 3.79-3.78 (m, 4H), 3.70-3.69 (m, 4H), 3.35-3.34 (m, 1H), 2.92and 2.91 (2s, 3H), 1.84-1.63 (m, 8H); Anal. Calcd. for C₂₃H₃₀F₂N₈O₄S: C,50.0; H, 5.5; N, 20.3. Found: C, 50.0; H, 5.4; N, 20.5%.

Example 80 Synthesis ofN-({1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}methyl)methanesulfonamide

Reaction of1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole(Example 2) and tert-butyl 4-piperidinylmethylcarbamate as in previousexamples gave tert-butyl{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}methylcarbamatein 94% yield: mp (CH₂Cl₂/MeOH) 210-212° C.; ¹H NMR (DMSO-d₆) δ 7.88 (d,J=8.1 Hz, 1H), 7.68 (t, J_(HF)=52.9 Hz, 1H), 7.40 (t, J=8.2 Hz, 1H),6.94 (d, J=7.9 Hz, 1H), 6.87 (t, J=5.5 Hz, 1H), 4.68-4.59 (m, 2H), 3.98(s, 3H), 3.80-3.78 (m, 4H), 3.70-3.69 (m, 4H), 3.05-2.87 (m, 2H), 2.90(t, J=5.9 Hz, 2H), 1.72 (br, 3H), 1.38 (s, 9H), 1.09 (br, 2H); Anal.Calcd. for C₂₇H₃₆F₂N₈O₄: C, 56.4; H, 6.3; N, 19.5. Found: C, 56.7; H,6.3; N, 19.6%.

Deprotection of the above carbamate with TFA in CH₂Cl₂ as in previousexamples gave{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}methylaminein 93% yield: ¹H NMR (DMSO-d₆) δ 7.89 (d, J=8.3 Hz, 1H), 7.68 (t,J_(HF)=52.9 Hz, 1H), 7.40 (t, J=8.2 Hz, 1H), 6.94 (d, J=7.8 Hz, 1H),4.71-4.62 (m, 2H), 3.98 (s, 3H), 3.80-3.78 (m, 4H), 3.70-3.69 (m, 4H),3.03-2.91 (m, 2H), 2.45 (d, J=6.4 Hz, 2H), 1.81 (br, 2H), 1.58-1.39 (m,3H), 1.10-1.05 (m, 2H).

Reaction of the above amine with methanesulfonyl chloride as in previousexamples gaveN-({1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}methyl)methanesulfonamidein 91% yield: mp (CH₂Cl₂/MeOH) 238-240° C.; ¹H NMR (DMSO-d₆) δ 7.89 (d,J=8.0 Hz, 1H), 7.69 (t, J_(HF)=52.9 Hz, 1H), 7.41 (t, J=8.2 Hz, 1H),7.03 (t, J=5.2 Hz, 1H), 6.95 (d, J=7.8 Hz, 1H), 4.71-4.61 (m, 2H), 3.98(s, 3H), 3.81-3.79 (m, 4H), 3.70-3.69 (m, 4H), 3.05-2.93 (m, 2H), 2.88(s, 3H), 2.88-2.85 (m, 2H), 1.82-1.76 (m, 3H), 1.19-1.12 (m, 2H); Anal.Calcd. for C₂₃H₃₀F₂N₈O₄S: C, 50.0, H, 5.5; N, 20.3. Found: C, 49.8; H,5.4; N, 20.3%.

Example 81 Synthesis ofN-({1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-piperidinyl}methyl)methanesulfonamide

Reaction of1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole(Example 2) with tert-butyl 3-piperidinylmethylcarbamate as in previousexamples gave tert-butyl{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-piperidinyl}methylcarbamatein 83% yield: mp (CH₂Cl₂/MeOH) 131-133° C.; ¹H NMR (DMSO-d₆) δ 7.93 and7.89 (2d, J=8.6, 8.4 Hz, 1H), 7.68 (t, J_(HF)=53.0 Hz, 1H), 7.46-7.38(m, 1H), 6.95 (d, J=8.1 Hz, 1H), 6.91 (br, 1H), 4.54-4.41 (m, 2H), 3.97(s, 3H), 3.79 (br s, 4H), 3.69 (br s, 4H), 3.14-3.05 (m, 1H), 2.94-2.76(m, 2H), 1.78-1.57 (m, 3H), 1.44-1.24 (m, 2H), 1.39 and 1.32 (2s, 9H);Anal. Calcd. for C₂₇H₃₆F₂N₈O₄: C, 56.4; H, 6.3; N, 19.5. Found: C, 56.6;H, 6.5; N, 19.5%.

Deprotection of the above carbamate with TFA in CH₂Cl₂ as in previousexamples gave{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-piperidinyl}methanaminein 93% yield: mp (CH₂Cl₂/hexanes) 202-204° C.; ¹H NMR (DMSO-d₆) δ 7.97and 7.89 (d, J=8.3, 8.2 Hz, 1H), 7.75 and 7.69 (2t, J_(HF)=52.8 Hz, 1H),7.42-7.36 (m, 1H), 6.94 (d, J=7.9 Hz, 1H), 4.58-4.34 (m, 2H), 3.97 (s,3H), 3.79-3.78 (m, 4H), 3.70-3.69 (m, 4H), 3.24-3.22 (m, 2H), 2.94-2.86(m, 1H), 2.54-2.44 (m, 1H), 1.84-1.71 (m, 2H), 1.45 (m, 4H), 1.31-1.23(m, 1H).

Reaction of the above amine with methanesulfonyl chloride as in previousexamples gaveN-({1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-piperidinyl}methyl)methanesulfonamidein 70% yield: mp (CH₂Cl₂/MeOH) 179-181° C.; ¹H NMR (DMSO-d₆) δ 7.97 and7.89 (2d, J=8.2 Hz, 1H), 7.71 and 7.69 (2t, J_(HF)=52.94, 53.2 Hz, 1H),7.47 and 7.41 (2t, J=8.2 Hz, 1H), 7.10 (br, 1H), 6.95 (d, J=8.00 Hz,1H), 4.64-4.38 (m, 2H), 3.98 (s, 3H), 3.79 (m, 4H), 3.70-3.69 (m, 4H),3.19-3.04 (m, 1H), 2.90-2.89 (m, 6H), 1.86-1.68 (m, 3H), 1.50-1.40 (m,1H), 1.36-1.26 (m, 1H); Anal. Calcd. for C₂₃H₃₀F₂N₈O₄S: C, 50.0; H, 5.5;N, 20.3. Found: C, 49.9; H, 5.5; N, 20.4%.

Example 82 Synthesis of4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-{[1-(methylsulfonyl)-4-piperidinyl]methyl}-6-(4-morpholinyl)-1,3,5-triazin-2-amine

Reaction of1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole(Example 2) with tert-butyl 4-(aminomethyl)-1-piperidinecarboxylate asin previous examples gave tert-butyl4-({[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}methyl)-1-piperidinecarboxylatein 91% yield: mp (CH₂Cl₂/MeOH) 203-205° C.; ¹H NMR (DMSO-d₆) δ 8.10-7.60(m, 3H), 7.41-7.36 (m, 1H), 6.94 (dd, J=7.8, 3.8 Hz, 1H), 3.974 and3.970 (2s, 3H), 3.95-3.92 (m, 2H), 3.78-3.77 (m, 4H), 3.69 (m, 4H),3.34-3.24 (m, 2H), 2.69 (m, 2H), 1.77-1.67 (m, 3H), 1.389 and 1.381 (2s,9H), 1.12-1.00 (m, 2H); Anal. Calcd. for C₂₇H₃₆F₂N₈O₄: C, 56.4; H, 6.3;N, 19.5. Found: C, 56.1; H, 6.3; N, 19.6%

Deprotection of the above carbamate with TFA in CH₂Cl₂ as in previousexamples gave4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-(4-piperidinylmethyl)-1,3,5-triazin-2-aminein 92% yield: mp (CH₂Cl₂/hexanes) 154-157° C.; ¹H NMR (DMSO-d₆) δ8.10-7.60 (m, 3H), 7.42-7.36 (m, 1H), 6.94 (dd, J=7.8, 5.4 Hz, 1H) 3.98and 3.97 (2s, 3H), 3.78-3.77 (m, 4H), 3.69 (m, 4H), 3.06-3.03 (m, 2H),2.94-2.92 and 2.81-2.78 (2m, 1H), 2.59-2.44 (m, 2H), 1.87-1.58 (m, 4H),1.25-1.09 (m, 2H).

Treatment of the above amine with methanesulfonyl chloride as inprevious examples gave4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-{[1-(methyl-sulfonyl)-4-piperidinyl]methyl}-6-(4-morpholinyl)-1,3,5-triazin-2-aminein 100% yield: mp (CH₂Cl₂/MeOH) 213-216° C.; ¹H NMR (DMSO-d₆) δ8.10-7.61 (m, 3H), 7.43-7.36 (m, 1H), 6.94 (dd, J=7.9, 4.4 Hz, 1H),3.98, 3.97 (2s, 3H), 3.79-3.76 (m, 4H), 3.69 (m, 4H), 2.59-3.56 (m, 2H),2.84 and 2.81 (2s, 3H), 2.71-2.62 (m, 2H), 1.83-1.69 (m, 3H), 1.31-1.18(m, 2H); Anal. Calcd. for C₂₃H₃₀F₂N₈O₄S: C, 50.0; H, 5.5; N, 20.2.Found: C, 49.9; H, 5.47; N, 20.3%.

Example 83 Synthesis ofN-[2-({4-[4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)ethyl]-N,N-dimethylamine

A mixture of 11 g (50 mmol) of benzyl 1-piperazinecarboxylate and 16.1 g(125 mmol) of DIPEA in 200 mL CH₂Cl₂ was cooled to −15° C. and 6.3 mL(9.8 g, 60 mmol) of 2-chloroethanesulfonyl chloride was added slowlyover 15 min. The mixture was allowed to warm to 0° C. over 30 min andwater was then added. The organic layer was separated and washedsuccessively with dil. HCl and aq. NaHCO₃. After drying, the solvent wasremoved and the residue was chromatographed on silica, eluting withCH₂Cl₂/EtOAc 95:5, to give an oil, which was recrystallized fromCH₂Cl₂/hexanes to give 6.64 g (43% yield) of benzyl4-(vinylsulfonyl)-1-piperazinecarboxylate: mp (CH₂Cl₂/hexanes) 85-87°C.; ¹H NMR (CDCl₃) δ 7.39-7.30 (m, 5H), 6.40 (dd, J=16.6, 9.8 Hz, 1H),6.25 (d, J=16.6 Hz, 1H), 6.06 (d, J=9.8 Hz, 1H), 5.14 (s, 2H), 3.61 (m,4H), 3.14 (m, 4H); Anal. Calcd. for C₁₄H₁₈N₂O₄S: C, 54.2; H, 5.85; N,9.0. Found: C, 54.1; H, 5.7; N, 9.1%.

A solution of the above vinylsulfonamide (3.10 g, 10 mmol) in 20 mL ofTHF was treated with an excess (10 mL, 80 mmol) of 40% aqueousdimethylamine. After 5 min, the mixture was diluted with water to give3.09 g (87% yield) of benzyl4-{[2-(dimethyl-amino)ethyl]sulfonyl}-1-piperazinecarboxylate as a whitesolid: mp (aq. MeOH) 101-103° C.; ¹H NMR (CDCl₃) δ 7.40-7.30 (m, 5H),5.15 (s, 2H), 3.59 (m, 4H), 3.26 (m, 4H), 3.07 (dd J=8.1, 6.4 Hz, 2H),2.74 (dd, J=8.0, 6.4 Hz, 2H), 2.25 (s, 6H); Anal. Calcd. forC₁₆H₂₅N₃O₄S: C, 54.1; H, 7.1; N, 11.8. Found: C, 53.8; H, 6.9; N, 11.8%.

Hydrogenation of the above carbamate in MeOH with 10% Pd on C gave aquantitative yield of N,N-dimethyl-2-(1-piperazinylsulfonyl)ethanamine,as an oil: ¹H NMR (CDCl₃) δ 3.26 (m, 4H), 3.08 (m, 2H), 2.94 (m, 3.5H),2.78 (m, 2H), 2.58 (m, 0.5H), 2.28 (s, 6H).

A mixture of the above amine (1.35 g, 6 mmol) and1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole(International Publ. No. WO 2002/088112, the disclosure of which isincorporated herein by reference in its entirety) (1.83 g, 5 mmol) andEt₃N (1.4 mL, 10 mmol) in 50 mL THF was stirred at room temperature for5 hrs and then diluted with water. The white solid was collected anddried. Chromatography on alumina, eluting with CH₂Cl₂ gave 1.42 g (43%yield) ofN-[2-({4-[4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)ethyl]-N,N-dimethylamine:¹H NMR (CDCl₃) δ 7.86 (br dd, J=7.1, 1.2 Hz, 1H), 7.89 (br dd, J=6.8,1.2 Hz, 1H), 7.53 (t, J_(HF)=53.5 Hz, 1H), 7.46-7.38 (m, 2H), 4.00 (m,4H), 3.89 (m, 4H), 3.79 (m, 4H), 3.40 (m, 4H), 3.21 (dd, J=8.1, 6.4 Hz,2H), 2.78 (dd, J=8.1, 6.4 Hz, 2H), 2.27 (s, 6H).

Hydrochloride: mp (MeOH/EtOAc) 244-246° C.; Anal. Calcd. forC₂₃H₃₂ClF₂N₉O₃S: C, 47.0; H, 5.5; N, 21.4; Cl, 6.0. Found: C, 47.1; H,5.5; N, 21.3; Cl, 6.3%.

Example 84 Synthesis ofN-[2-({4-[4-[6-amino-2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)ethyl]-N,N-dimethylamine

A mixture of 293 mg (0.57 mmol) of tert-butyl1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazol-6-yl-carbamate(Example 9), 152 mg (0.69 mmol) ofN,N-dimethyl-2-(1-piperazinylsulfonyl)ethanamine (Example 83), and 87 mg(0.86 mmol) of Et₃N in 20 mL THF was stirred at room temperature for 2hrs. The solvent was removed under vacuum. After dilution with water,the residue was extracted into CH₂Cl₂ and dried. Removal of the solventgave a white solid which was recrystallized from methanol to give 0.27g, (68% yield) of tert-butyl2-(difluoromethyl)-1-[4-(4-{[2-(dimethylamino)ethyl]sulfonyl}-1-piperazinyl)-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-methoxy-1H-benzimidazol-6-ylcarbamate:mp 200-202° C.; ¹H NMR (CDCl₃) δ 8.63 (br s, 1H), 7.44 (t, J_(HF)=53.6Hz, 1H), 6.62 (br s, 1H), 6.36 (d, J=1.6 Hz, 1H), 4.12-3.77 (m, 15H),3.40 (m, 4H), 3.10 (dd, J=8.2, 6.4 Hz, 2H), 2.77 (dd, J=8.2, 6.4 Hz,2H), (s, 6H), 1.52 (s, 9H); Anal. Calcd. for C₂₉H₄₂F₂N₁₀O₆S: C, 50.0; H,6.1; N, 20.1. Found: C, 50.3; H, 6.15; N, 20.1%.

A solution of the above carbamate (0.244 g, 0.035 mmol) in a mixture of10 mL CH₂Cl₂ and 5 mL TFA was stirred at room temperature for 2 hrs. Themixture was diluted with CH₂Cl₂ and then made basic with dil. aq. NH₃.The organic layer was dried and concentrated to give a quantitativeyield ofN-[2-({4-[4-[6-amino-2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)ethyl]-N,N-dimethylamine:¹H NMR (CDCl₃) δ 7.35 (t, J_(HF)=53.8 Hz, 1H), 7.15 (d, J=1.9 Hz, 1H),6.22 (d, J=1.9 Hz, 1H), 3.98 (m, 7H), 3.90-3.75 (m, 10H), 3.38 (m, 4H),3.11 (dd, J=8.1, 6.5 Hz, 2H), 2.78 (dd, J=8.1, 6.4 Hz, 2H), 2.26 (s,6H).

Dimethanesulfonate: mp (MeOH/EtOAc) 238° C. dec.; Anal. Calcd. forC₂₆H₄₂F₂N₁₀O₁₀S₃.1.5 H₂O: C, 38.3; H, 5.6; N, 17.2. Found: C, 38.1; H,5.6; N, 17.1%.

Example 85 Synthesis of2-(difluoromethyl)-4-methoxy-1-{4-[4-(methylsulfonyl)-1-piperazinyl]-6-tetrahydro-2H-pyran-4-yl-1,3,5-triazin-2-yl}-1H-benzimidazole

A mixture of 2-(difluoromethyl)-4-methoxy-1H-benzimidazole (Example 2)(0.99 g, 5 mmol), tert-butyl4-(4,6-dichloro-1,3,5-triazin-2-yl)piperazine-1-carboxylate (Lowik etal, Eur. J. Org. Chem., 2001, 2825) (2.0 g, 6 mmol), and 3.5 g (25 mmol)powdered K₂CO₃ in 40 mL DMF was stirred at room temperature for 1 hr.Water was added, and the product was collected by filtration and washedwith water and cold ethanol to give 2.14 g (86% yield) of tert-butyl4-(4-chloro-6-(2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl)-1,3,5-triazin-2-yl)piperazine-1-carboxylate:mp (CH₂Cl₂/EtOH)>300° C.; ¹H NMR (CDCl₃) δ7.99 (d, J=8.3 Hz, 1H), 7.48(t, J_(HF)=53.4 Hz, 1H), 7.41 (t, J=8.3 Hz, 1H), 6.87 (d, J=8.0 Hz, 1H),4.06 (s, 3H), 3.95 (m, 4H), 3.58 (m, 4H), 1.50 (s, 9H); Anal. Calcd. forC₂₁H₂₄ClF₂N₇O₃: C, 50.9; H, 4.9; N, 19.8. Found: C, 51.1; H, 4.9; N,19.95%.

A mixture of the above chloro compound (800 mg, 1.61 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran(400 mg, 1.90 mmol), PdCl₂(dppf) (66 mg, 0.081 mmol), and K₂CO₃ (445 mg,3.22 mmol) in 1,4-dioxane/H₂O (60 mL/15 mL) was refluxed under nitrogenfor 1 hr. The mixture was cooled to room temperature and diluted withwater. The aqueous phase was extracted with CH₂Cl₂ (3×). The combinedorganic extracts were dried (Na₂SO₄) and the solvent was removed undervacuum. Chromatography on silica eluting with CH₂Cl₂/MeOH (100:0 to98:2) gave tert-butyl4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(3,6-dihydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl]-1-piperazinecarboxylate(371 mg, 42%): ¹H NMR (CDCl₃) δ 8.00 (d, J=8.1 Hz, 1H), 7.56 (t,J_(HF)=53.5 Hz, 1H), 7.44 (m, 1H), 7.39 (t, J=8.2 Hz, 1H), 6.85 (d,J=7.9 Hz, 1H), 4.44 (q, J=2.8 Hz, 2H), 4.06 (s, 3H), 4.01 (m, 2H), 3.94(t, J=5.4 Hz, 4H), 3.58 (br s, 4H), 2.68 (m, 2H), 1.51 (s, 9H).

A mixture of the above dihydro compound (371 mg, 0.683 mmol) and 10%Pd/C in THF/MeOH (90 mL:10 mL) was hydrogenated for 27 hrs. The reactionmixture was filtered through celite and the solvents were removed undervacuum. Chromatography on silica eluting with CH₂Cl₂/MeOH (100:0 to99:1) followed by chromatography on silica eluting with CH₂Cl₂/MeOH(99.75:0.25 to 99.25:0.75) gave tert-butyl4-{4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-tetrahydro-2H-pyran-4-yl-1,3,5-triazin-2-yl}-1-piperazinecarboxylate(154 mg, 41%): mp (CH₂Cl₂/MeOH) 203-204° C.; ¹H NMR (CDCl₃) δ 8.03 (d,J=8.1 Hz, 1H), 7.59 (t, J=53.6 Hz, 1H), 7.39 (t, J=8.2 Hz, 1H), 6.85 (d,J=8.2 Hz, 1H), 4.11 (dt, J=11.4, 3.3 Hz, 2H), 4.06 (s, 3H), 3.99 (m,2H), 3.92 (m, 2H), 3.59-3.53 (m, 6H), 2.93 (ddd, J=18.0, 8.9, 7.0 Hz,1H), 1.99 (m, 4H), 1.50 (s, 9H).

Reaction of the above carbamate (144 mg, 0.264 mmol) with an excess ofTFA (0.6 mL) in CH₂Cl₂ (3 mL) at room temperature for 30 minutes,followed by treatment with aq. NH₃ gave2-(difluoromethyl)-4-methoxy-1-[4-(1-piperazinyl)-6-tetrahydro-2H-pyran-4-yl-1,3,5-triazin-2-yl]-1H-benzimidazole(113 mg, 96%): ¹H NMR (CDCl₃) δ 8.04 (dd, J=8.4, 0.6 Hz, 1H), 7.62 (t,T_(HF)=53.6 Hz, 1H), 7.38 (t, J=8.2 Hz, 1H), 6.84 (d, J=7.7 Hz, 1H),4.10 (dt, J=11.4, 3.4 Hz, 2H), 4.05 (s, 3H), 3.98 (t, J=4.8 Hz, 2H),3.92 (t, J=4.8 Hz, 2H), 3.56 (m, 2H), 2.98 (m, 4H), 2.91 (m, 1H), 1.99(m, 4H).

Methanesulfonyl chloride (0.07 mL, 0.904 mmol) was added drop-wise to amixture of the above amine (102 mg, 0.229 mmol) and powdered K₂CO₃ (253mg, 1.83 mmol) in CH₂Cl₂ (5 mL) at 0° C. The reaction mixture wasstirred at 0° C. for 5 min and allowed to warm to room temperature.After 5 hrs, additional K₂CO₃ (127 mg, 0.919 mmol) and methanesulfonylchloride (0.04 mL, 0.517 mmol) were added and the mixture stirred atroom temperature for another 16 hrs. Water was added and the layers wereseparated. The organic layer was dried (Na₂SO₄) and the solvent wasremoved under vacuum. Recrystallization from CH₂Cl₂/MeOH gave2-(difluoromethyl)-4-methoxy-1-{4-[4-(methylsulfonyl)-1-piperazinyl]-6-tetrahydro-2H-pyran-4-yl-1,3,5-triazin-2-yl}-1H-benzimidazole(73 mg, 61%): mp (CH₂Cl₂/MeOH) 242-244° C.; ¹H NMR (CDCl₃) δ 8.00 (dd,J=8.4, 0.6 Hz, 1H), 7.55 (t, J_(HF)=53.5, 1H), 7.40 (t, J=7.9 Hz, 1H),6.86 (d, J=7.7 Hz, 1H), 4.14-4.09 (m, 6H), 4.06 (s, 3H), 3.56 (m, 2H),3.37 (br s, 4H), 2.96 (m, 1H), 2.83 (s, 3H), 1.99 (ddd, J=12.1, 7.9,4.0, 4H); Anal. Calcd. for C₂₂H₂₇F₂N₇O₄S: C, 50.5; H, 5.2; N, 18.7.Found: C, 50.6; H, 5.4; N, 18.6%.

Example 86 Synthesis of2-(difluoromethyl)-4-methoxy-1-(4-(4-morpholinyl)-6-{4-[(trifluoromethyl)-sulfonyl]-1-piperazinyl}-1,3,5-triazin-2-yl)-1H-benzimidazole

To a mixture of 223 mg (0.5 mmol) of2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole(Example 2) and 126 mg (1.25 mmol) of Et₃N in 10 mL CH₂Cl₂ at −78° C.was added 126 μL (211 mg, 0.75 mmol) of trifluoromethanesulfonicanhydride. The mixture was allowed to warm slowly to 0° C. After 30 min,water was added. The organic layer was separated, dried, andconcentrated under vacuum. Recrystallization of the residue fromCH₂Cl₂/MeOH gave 240 mg (83% yield) of2-(difluoromethyl)-4-methoxy-1-(4-(4-morpholinyl)-6-{4-[(trifluoromethyl)sulfonyl]-1-piperazinyl}-1,3,5-triazin-2-yl)-1H-benzimidazole:mp 272-273° C.; ¹H NMR (CDCl₃) δ 7.84 (dd, J=8.4, 0.6 Hz, 1H), 7.40 (t,J_(HF)=53.5 Hz, 1H), 7.36 (t, J=8.2 Hz, 1H), 6.83 (d, J=7.7 Hz, 1H),4.15-3.93 (m, 7H), 3.89 (m, 4H), 3.79 (m, 4H), 3.61 (m, 4H); ¹⁹F NMR(CDCl₃) δ−75.5 (s), −116.6 (d, J=0.11 Hz); Anal. Calcd. forC₂₁H₂₃F₅N₈O₄S: C, 43.6; H, 4.0; N, 19.4. Found: C, 44.1; H, 4.0; N,19.7%.

Example 87 Synthesis ofN-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}trifluoromethanesulfonamide

To a mixture of 0.76 g (1.55 mmol) of1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinamine(Example 17) and 0.4 g (4.0 mmol) of Et₃N in 40 mL CH₂Cl₂ at −78° C. wasadded 0.42 mL (0.7 g, 2.5 mmol) of trifluoromethanesulfonic anhydride.The mixture was allowed to warm slowly to 0° C. After 30 min water wasadded. After acidification with dil. HCl, the organic layer wasseparated, dried, and concentrated under vacuum. Recrystallization ofthe residue from CH₂Cl₂/MeOH gave 0.87 g (89% yield ofN-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}(trifluoro)methanesulfonamide:mp 282-285° C.; ¹H NMR (DMSO-d₆) δ 9.51 (br s, 1H), 7.88 (d, J=8.1 Hz,1H), 7.68 (t, J_(HF)=52.9 Hz, 1H), 7.41 (t, J=8.2 Hz, 1H), 6.95 (d,J=7.9 Hz, 1H), 4.57 (m, 2H), 3.98 (s, 3H), 3.80 (m, 4H), 3.69 (m, 5H),3.22 (m, 2H), 1.95 (m, 2H), 1.51 (br dd, J=20.5, 10.1 Hz, 2H); ¹⁹F NMR(DMSO-d₆) δ −78.1 (s), −116.6 (dd, J=0.15, 0.03 Hz); Anal. Calcd. forC₂₂H₂₅F₅N₈O₄S: C, 44.6; H, 4.25; N, 18.9. Found: C, 44.5; H, 4.2; N,19.2%.

Example 88 Synthesis ofN-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-azetidinyl}(trifluoro)methanesulfonamide

To a suspension of1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-azetidinamine(Example 30) (303 mg, 0.7 mmol) and Et₃N (0.4 ml, 4 eq.) in CH₂Cl₂ (15mL) at −78° C. was added trifluoromethanesulfonic anhydride (2 eq.) andthe resulting mixture was stirred at −78° C. for 1 hr. The reactionmixture was quenched with MeOH and diluted with aqueous K₂CO₃ (10 mL)and stirred overnight at room temperature. After neutralization withdil. HCl, the MeOH was evaporated under vacuum and the resultingprecipitate was filtered, washed with water and recrystallized from(CH₂Cl₂/MeOH) to giveN-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-azetidinyl}(trifluoro)methanesulfonamide(288 mg, 73%): mp (CH₂Cl₂/MeOH); ¹H NMR (DMSO-d₆) δ 10.42 (br 1H), 7.97(d, J=8.0 Hz, 1H), 7.73 (t, J_(HF)=53.0 Hz, 1H), 7.41 (t, J=8.2 Hz, 1H),6.95 (d, J=7.9 Hz, 1H), 4.52-4.44 (m, 3H), 4.07-3.97 (m, 2H), 3.97 (s,3H), 3.80-3.78 (m, 4H), 3.68 (m, 4H); Anal. Calcd. for C₂₀H₂₁F₅N₈O₄S: C,42.6; H, 3.6; N, 19.9. Found: C, 42.6; H, 3.7; N, 20.0%.

Example 89 Synthesis of4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N,N-dimethyl-1-piperazinesulfonamide

A solution of 224 mg (0.5 mmol) of2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole(Example 2) and 130 mg (1 mmol) of DIPEA in 10 mL of CH₂Cl₂ was treatedwith 150 mg (1 mmol) of dimethylsulfamoyl chloride and the mixture wasstirred at room temperature overnight. Water was added, and the organiclayer was separated and dried. Chromatography on silica, eluting withCH₂Cl₂/EtOAc (9:1), gave 217 mg (78% yield) of4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N,N-dimethyl-1-piperazinesulfonamide:mp (MeOH) 286-288° C.; ¹H NMR (CDCl₃) δ 7.86 (dd, J=8.4, 0.7 Hz, 1H),7.44 (t, J=53.5 Hz, 1H), 7.35 (t, J=8.2 Hz, 1H), 6.82 (d, J=7.7 Hz, 1H),4.05 (s, 3H), 3.96 (m, 4H), 3.89 (m, 4H), 3.78 (m, 4H), 3.34 (m, 4H),2.87 (s, 6H); Anal. Calcd. for C₂₂H₂₉F₂N₉O₄S: C, 47.7; H, 5.3; N, 22.8.Found: C, 47.95; H, 5.3; N, 22.9%.

Example 90 Synthesis of1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N,N-dimethyl-4-piperidinesulfonamide

A solution of 190 mg (0.6 mmol) of benzyl4-(chlorosulfonyl)-1-piperidinecarboxylate in 10 mL THF was treated witha 10-fold excess of 40% aq. dimethylamine and the mixture was stirred atroom temperature for 2 hrs. The THF was removed under vacuum. Theresidue was diluted with water, extracted with CH₂Cl₂, and dried.Chromatography on alumina, eluting with CH₂Cl₂, gave 175 mg (89% yield)of benzyl 4-[(dimethylamino)sulfonyl]-1-piperidinecarboxylate as an oil:¹H NMR (CDCl₃) δ 7.40-7.30 (m, 5H), 5.13 (s, 2H), 4.31 (m, 2H), 3.10(tt, J=12.0, 3.7 Hz, 1H), 2.92 (s, 6H), 2.85-2.75 (m, 2H), 2.04 (br d,J=13.7 Hz, 2H), 1.76 (dq, J=12.6, 4.5 Hz, 2H).

The above carbamate was hydrogenated over 5% Pd on carbon in MeOH. Afterremoval of the solvent, the residue was combined with 0.19 g (0.48 mmol)1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole(Example 2) and DIPEA in THF. The mixture was heated under reflux for 30min and the solvent was removed. After dilution with water, theresulting solid was collected and dried. Chromatography on silica,eluting with CH₂Cl₂/EtOAc (93:7), gave 0.227 g (86% yield) of1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N,N-dimethyl-4-piperidinesulfonamide:mp (MeOH) 260-264° C.; ¹H NMR (CDCl₃) δ 7.88 (dd, J=8.4, 0.6 Hz, 1H),7.46 (t, J_(HF)=53.5 Hz, 1H), 7.35 (t, J=7.7 Hz, 1H), 6.81 (d, J=7.7 Hz,1H), 4.91 (br d, J=13.5 Hz, 2H), 4.05 (s, 3H), 3.88 (m, 4H), 3.78 (m,4H), 3.27 (tt, J=11.8, 3.8 Hz, 1H), 2.95 (s, 6H), 2.17 (dd, J=12.7, 2.2Hz, 2H), 1.85 (dq, J=12.6, 4.2 Hz, 2H); Anal. Calcd. for C₂₃H₃₀F₂N₈O₄S:C, 50.0; H, 5.5; N, 20.3. Found: C, 49.9; H, 5.5; N, 20.4%.

Example 91 Synthesis of1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N-methyl-4-piperidinesulfonamide

A solution of 190 mg (0.6 mmol) of benzyl4-(chlorosulfonyl)-1-piperidinecarboxylate in 10 mL THF was treated witha 10-fold excess of 40% aq. methylamine and the mixture was stirred atroom temperature for 2 hrs. The THF was removed under vacuum. Afterdilution with water, the resulting solid was collected and dried to give260 mg (83% yield) of benzyl4-[(methylamino)sulfonyl]-1-piperidinecarboxylate: mp (aq. MeOH)124-126° C.; ¹H NMR (CDCl₃) δ 7.40-7.30 (m, 5H), 5.13 (s, 2H), 4.34 (m,2H), 4.01 (dd, J=10.2, 5.0 Hz, 1H), 3.05 (tt, J=11.9, 3.7 Hz, 1H),2.87-2.77 (m, 5H), 2.11 (br d, J=12.9 Hz, 2H), 1.75 (dq, J=12.6, 4.5 Hz,2H). Anal. Calcd. for C₁₄H₂₀N₂O₄S: C, 53.8; H, 6.45; N, 9.0. Found: C,53.75; H, 6.5; N, 9.0%.

The above carbamate was hydrogenated over 5% Pd on carbon in MeOH. Afterremoval of the solvent, the residue was combined with 0.19 g (0.48 mmol)1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole(Example 2) and DIPEA in THF. The mixture was heated under reflux for 30min and the solvent was concentrated. After dilution with water, theresulting solid was collected and dried. Chromatography on alumina,eluting with CH₂Cl₂/EtOAc (9:1), gave 0.127 g (39% yield) of1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N-methyl-4-piperidinesulfonamide:mp (MeOH) 261-263° C.; ¹H NMR (CDCl₃) δ 7.87 (dd, J=8.4, 0.6 Hz, 1H),7.46 (t, J_(HF)=53.6 Hz, 1H), 7.35 (t, J=8.0 Hz, 1H), 6.82 (d, J=7.7 Hz,1H), 4.93 (br d, J=13.5 Hz, 2H), 4.05 (s, 3H), 4.02 (q, J=5.3 Hz, 1H),3.88 (m, 4H), 3.78 (m, 4H), 3.22 (tt, J=11.8, 3.7 Hz, 1H), 3.00 (m, 2H),2.86 (d, J=5.3 Hz, 3H), 2.24 (br d, J=12.0 Hz, 2H), 1.85 (dq, J=12.5,4.4 Hz, 2H); Anal. Calcd. for C₂₂H₂₈F₂N₈O₄S: C, 49.1; H, 5.2; N, 20.8.Found: C, 49.2; H, 5.3; N, 21.0%.

Example 92 Synthesis of1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N-[2-(dimethylamino)ethyl]-4-piperidinesulfonamide

A solution of 430 mg (1.35 mmol) of benzyl4-(chlorosulfonyl)-1-piperidinecarboxylate in 10 mL THF was treated witha 5-fold excess of N,N-dimethyl-ethylenediamine and the mixture wasstirred at room temperature for 2 hrs. The THF was removed under vacuum.After dilution with water, the product was extracted with CH₂Cl₂ anddried. Chromatography on alumina, eluting with EtOAc, gave 450 mg (90%yield) of benzyl4-({[2-(dimethylamino)ethyl]amino}sulfonyl)-1-piperidinecarboxylate asan oil: ¹H NMR (CDCl₃) δ 7.40-7.30 (m, 5H), 5.13 (s, 2H), 4.33 (m,exchangeable with D₂O, 1H), 3.16 (m, 2H), 3.04 (tt, J=11.9, 3.7 Hz, 1H),2.81 (br t, J=11.9 Hz, 1H), 2.43 (m, 2H), 2.22 (s, 6H), 2.12 (br d,J=12.8 Hz, 2H), 1.74 (ddd, J=25.0, 12.6, 4.5 Hz, 2H).

The above carbamate was hydrogenated over 5% Pd on carbon in MeOH. Afterremoval of the solvent, the residue was combined with 0.48 g (1.2 mmol)1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole(Example 2) and 0.35 g (2.7 mmol) DIPEA in THF. The mixture was heatedunder reflux for 1 hr and the solvent was concentrated. After dilutionwith water, the resulting solid was collected and dried. Chromatographyon alumina, eluting with EtOAc, gave1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N-[2-(dimethylamino)ethyl]-4-piperidinesulfonamide:mp (MeOH) 231-234° C.; ¹H NMR (CDCl₃) δ 7.87 (dd, J=8.4, 0.6 Hz, 1H),7.47 (t, J_(HF)=53.5 Hz, 1H), 7.35 (t, J=8.2 Hz, 1H), 6.81 (d, J=7.8 Hz,1H), 4.91 (br d, J=13.3 Hz, 2H), 4.04 (s, 3H), 3.88 (m, 4H), 3.78 (m,4H), 3.25-3.17 (m, 3H), 3.00 (m, 2H), 2.45 (br t, J=5.7 Hz, 2H), 2.27(m, 2H), 2.23 (s, 6H), 1.83 (dq, J=12.5, 4.4 Hz, 2H); Anal. Calcd. forC₂₅H₃₅F₂N₉O₄S: C, 50.4; H, 5.9; N, 21.2. Found: C, 50.2; H, 5.7; N,21.3%.

Example 93 Synthesis of1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N-methyl-3-pyrrolidinesulfonamide

Methylamine (40 wt % in H₂O, 1 mL) was added to a solution of3-chlorosulfonyl-pyrrolidine-1-carboxylic acid benzyl ester (256 mg,0.843 mmol) in THF (1 mL) at 0° C. The mixture was stirred at 0° C. for10 min, and then warmed to room temperature and stirred for 2 hrs. Waterwas added and the phases were separated. The aqueous phase was extractedwith CH₂Cl₂ (2×), the combined organic extracts were dried (Na₂SO₄), andthe solvent was removed under vacuum. Chromatography on neutral alumina,eluting with CH₂Cl₂/MeOH (99:1 to 95:5), gave benzyl3-[(methylamino)sulfonyl]-1-pyrrolidinecarboxylate (173 mg, 69%): ¹H NMR(CDCl₃) δ 7.36-7.29 (m, 5H), 5.14 (d, J=1.9 Hz, 2H), 4.27 (d, J=42.6 Hz,1H), 3.80-3.70 (m, 4H), 3.50 (m, 1H), 2.82 (d, J=4.9 Hz, 3H), 2.35 (m,2H).

A mixture of the above benzyl carbamate (173 mg, 0.580 mmol) and 10% Pdon carbon in MeOH (15 mL) was hydrogenated for 24 hrs. The reactionmixture was filtered through celite, the celite pad was washed withMeOH, and the solvent was removed under vacuum to giveN-methyl-3-pyrrolidinesulfonamide (92 mg, 97%) which was used in thenext step without further purification. ¹H NMR (DMSO-d₆) δ 6.89 (br s,1H), 3.62 (qd, J=8.9, 6.3 Hz, 1H), 2.99 (m, 2H), 2.82 (m, 1H), 2.72 (m,1H), 2.59 (s, 3H), 1.95 (m, 2H).

DIPEA (0.15 mL, 0.861 mmol) was added to a stirred suspension of1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole(Example 2) (174 mg, 0.438 mmol) and the above amine (90 mg, 0.548 mmol)in THF (15 mL) at room temperature, and the mixture was stirred for 19hrs. The solvent was removed under vacuum and the residue waspartitioned between H₂O and CH₂Cl₂. The aqueous phase was extracted withCH₂Cl₂ (2×), the combined organic extracts were dried (Na₂SO₄), and thesolvent was removed under vacuum. Chromatography on silica, eluting withCH₂Cl₂/MeOH (100:0 to 98:2), gave1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N-methyl-3-pyrrolidinesulfonamide(201 mg, 87%): mp (CH₂Cl₂/MeOH) 260-261° C.; ¹H NMR (DMSO-d₆) δ 8.00(dd, J=8.3, 3.2 Hz, 1H), 7.76 (t, J_(HF)=53.0 Hz, 1H), 7.41 (dt, J=8.3,1.3 Hz, 1H), 7.25 (br s, 1H), 6.95 (dd, J=8.1, 1.4 Hz, 1H), 4.07 (m,1H), 3.98 (s, 3H), 3.98-3.95 (m, 1H), 3.88 (d, J=6.5 Hz, 1H), 3.86-3.63(m, 10H), 2.65 (s, 3H), 2.35 (m, 2H); Anal. Calcd. for C₂₁H₂₆F₂N₈O₄S: C,48.1; H, 5.0; N, 21.4. Found: C, 48.4; H, 5.1; N, 21.1%.

Example 94 Synthesis of1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N-[2-(dimethylamino)ethyl]-3-pyrrolidinesulfonamide

A solution of 3-chlorosulfonyl-pyrrolidine-1-carboxylic acid benzylester (110 mg, 0.362 mmol) in CH₂Cl₂ (1.5 mL) was added to a solution ofN,N-dimethylethylenediamine (0.20 mL, 1.83 mmol) in CH₂Cl₂ (1 mL) at 0°C. The mixture was stirred at 0° C. for 10 min, and then warmed to roomtemperature and stirred for 1 hr. Water was added and the phases wereseparated. The aqueous phase was extracted with CH₂Cl₂ (2×), thecombined organic extracts were dried (Na₂SO₄), and the solvent wasremoved under vacuum to give benzyl3-({[2-(dimethylamino)ethyl]amino}sulfonyl)-1-pyrrolidinecarboxylate(102 mg, 88%), which was used in the next step without furtherpurification: ¹H NMR (CDCl₃) δ 7.36-7.29 (m, 5H), 5.14 (d, J=1.8 Hz,2H), 3.80-3.72 (m, 4H), 3.50 (m, 1H), 3.16 (br s, 2H), 2.42 (t, J=5.7Hz, 2H), 2.31 (m, 2H), 2.21 (s, 6H).

A mixture of the above benzyl carbamate (171 mg, 0.481 mmol) and 10% Pdon carbon in MeOH (15 mL) was hydrogenated for 29 hrs. The reactionmixture was filtered through celite, the celite pad was washed withMeOH, and the solvent was removed under vacuum to giveN-[2-(dimethylamino)ethyl]-3-pyrrolidinesulfonamide (94 mg, 89%), whichwas used in the next step without further purification: ¹H NMR (DMSO-d₆)δ 6.93 (br s, 1H), 3.62 (m, 1H), 3.04-2.99 (m 4H), 2.83 (m, 1H), 2.72(m, 1H), 2.31 (t, J=6.8 Hz, 2H), 2.14 (s, 6H), 1.92 (m, 2H).

DIPEA (0.11 mL, 0.632 mmol) was added to a stirred suspension of1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole(Example 2) (127 mg, 0.320 mmol) and the above amine (92 mg, 0.416 mmol)in THF (10 mL) at room temperature and the mixture stirred for 2.5 days.The solvent was removed under vacuum, and the residue was partitionedbetween H₂O and CH₂Cl₂. The aqueous phase was extracted with CH₂Cl₂(1×), the combined organic fractions were dried (Na₂SO₄), and thesolvent was removed under vacuum. Recrystallization from CH₂Cl₂/hexanes,followed by chromatography on silica, eluting with CH₂Cl₂/MeOH (100:0 to95:5), gave1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N-[2-(dimethylamino)ethyl]-3-pyrrolidinesulfonamide(92 mg, 49%).

Treatment with methanesulfonic acid in CH₂Cl₂/MeOH and recrystallizationfrom MeOH/EtOAc gave a methanesulfonate salt: mp 196-199° C.; ¹H NMR(DMSO-d₆) δ 9.34 (br s, 1H), 8.00 (dd, J=8.2, 5.4 Hz, 1H), 7.77 (m, 1H),7.77 (t, J_(HF)=53.1 Hz, 1H), 7.41 (t, J=8.2 Hz, 1H), 6.96 (d, J=8.2 Hz,1H), 4.16 (m, 1H), 3.40-3.95 (m, 1H), 3.98 (s, 3H), 3.91 (d, J=6.6 Hz,1H), 3.87-3.66 (m, 10H), 3.38 (q, J=6.1 Hz, 2H), 3.19 (t, J=6.3 Hz, 2H),2.82 (d, J=1.8 Hz, 6H), 2.39 (m, 2H), 2.31 (s, 3H); Anal. Calcd. forC₂₅H₃₇F₂N₉O₇S₂.0.6H₂O: C, 43.6; H, 5.6; N, 18.3. Found: C, 43.4; H, 5.6;N, 18.3%.

Example 95 Synthesis of2-(difluoromethyl)-4-methoxy-1-[4-{4-[(4-methyl-1-piperazinyl)sulfonyl]phenyl}-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole

A mixture of1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole(Example 2) (200 mg, 0.504 mmol),4-[(4-methyl-1-piperazinyl)sulfonyl]phenylboronic acid (186 mg, 0.655mmol), PdCl₂(dppf) (29 mg, 0.0355 mmol), and aq. K₂CO₃ (2M, 3 mL) in1,4-dioxane (20 mL) was refluxed under nitrogen for 1 hr. The mixturewas cooled to room temperature and diluted with H₂O, and the aqueousphase extracted with CH₂Cl₂ (9×). The combined organic extracts weredried (Na₂SO₄), and the solvent was removed under vacuum. Chromatographyon alumina, eluting with CH₂Cl₂/MeOH (100:0 to 99.75:0.25), followed bychromatography on silica, eluting with CH₂Cl₂/MeOH (100:0 to 98:2), andrecrystallization from CH₂Cl₂/MeOH/hexanes gave2-(difluoromethyl)-4-methoxy-1-[4-{4-[(4-methyl-1-piperazinyl)sulfonyl]phenyl}-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole(93 mg, 31%).

Treatment with methanesulfonic acid in CH₂Cl₂/MeOH and recrystallizationfrom MeOH/EtOAc gave a methanesulfonate salt: mp 289-292° C.; ¹H NMR(DMSO-d₆) δ 9.36 (br s, 1H), 8.71 (d, J=8.6 Hz, 2H), 8.08 (d, J=8.0 Hz,1H), 8.03 (d, J=8.6 Hz, 2H), 7.83 (t, J_(HF)=52.7 Hz, 1H), 7.50 (t,J=8.2 Hz, 1H), 7.03 (d, J=8.0 Hz, 1H), 4.09 (m, 2H), 4.00 (s, 3H), 3.96(m, 2H), 3.81-3.79 (m, 6H), 3.47 (br s, 2H), 3.19 (br s, 2H), 2.79 (brs, 3H), 2.65 (br s, 2H), 2.29 (s, 3H); Anal. Calcd. for C₂₈H₃₄F₂N₈O₇S₂:C, 48.3; H, 4.9; N, 16.1. Found: C, 48.1; H, 5.1; N, 15.9%.

Example 96 Synthesis of2-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-9-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-7,9-dihydro-8H-purin-8-one

Powdered K₂CO₃ (1.305 g, 9.44 mmol) was added to a stirred suspension oftert-butyl4-{[2-chloro-6-(4-morpholinyl)-5-nitro-4-pyrimidinyl]amino}-1-piperidinecarboxylate(U.S. Pat. Appl. Publ. No. 2009/0181963, the disclosure of which isincorporated herein by reference in its entirety) (1.047 g, 2.36 mmol)and 2-difluoromethyl-4-methoxy-1H-benzimidazole (Example 2) (608 mg,3.07 mmol) in DMF (70 mL) at room temperature, and the mixture wasstirred for 2.5 days. The reaction mixture was diluted with water, andthe resulting precipitate was collected by filtration and dried.Recrystallization from CH₂Cl₂/MeOH gave tert-butyl4-{[2-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-5-nitro-4-pyrimidinyl]amino}-1-piperidinecarboxylate(1.27 g, 89%): mp 229-231° C.; ¹H NMR (CDCl₃) δ 8.64 (d, J=7.7 Hz, 1H),7.81 (dd, J=8.4, 0.6 Hz, 1H), 7.36 (t, J_(HF)=53.5 Hz, 1H), 7.36 (t,J=8.2 Hz, 1H), 6.84 (d, J=7.7 Hz, 1H), 4.36 (m, 1H), 4.11 (m, 2H), 4.06(s, 3H), 3.85 (t, J=4.9 Hz, 4H), 3.65 (t, J=4.6 Hz, 4H), 3.01 (t, J=11.5Hz, 2H), 2.08 (m, 2H), 1.64-1.51 (m, 2H), 1.48 (s, 9H); Anal. Calcd. forC₂₇H₃₄F₂N₈O₆: C, 53.6; H, 5.7; N, 18.5. Found: C, 53.35; H, 5.7; N,18.8%.

A mixture of the above nitro compound (700 mg, 1.16 mmol) and 10% Pd oncarbon in MeOH/THF (70 mL: 15 mL) was hydrogenated for 5 hrs. Thereaction mixture was filtered through celite, the celite pad was washedwith MeOH and CH₂Cl₂, and the solvents were removed under vacuum.Recrystallization from CH₂Cl₂/MeOH gave tert-butyl4-{[5-amino-2-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-pyrimidinyl]amino}-1-piperidinecarboxylate(622 mg, 94%): mp 223-225° C.; ¹H NMR (CDCl₃) δ 7.92 (dd, J=8.4, 0.6 Hz,1H), 7.54 (t, J_(HF)=53.7 Hz, 1H), 7.32 (t, J=8.2 Hz, 1H), 6.79 (d,J=7.6 Hz, 1H), 4.68 (d, J=7.6 Hz, 1H), 4.23-4.10 (m, 3H), 4.05 (s, 3H),3.89 (m, 4H), 3.25 (m, 4H), 3.06 (br s, 2H), 2.96 (t, J=12.0 Hz, 2H),2.11 (m, 2H), 1.47 (s, 9H), 1.50-1.40 (m, 2H); Anal. Calcd. forC₂₇H₃₆F₂N₈O₄: C, 56.4. H, 6.3; N, 19.5. Found: C, 56.3; H, 6.4; N,19.7%.

1,1′-Carbonyldiimidazole (689 mg, 4.25 mmol) was added to a solution ofthe above amine (244 mg, 0.425 mmol) in 1,4-dioxane (25 mL) and themixture was refluxed under nitrogen for 4.5 hrs. Additional1,1′-carbonyldiimidazole (689 mg, 4.25 mmol) was added, and the mixturerefluxed for additional 17.5 hrs. The mixture was cooled to roomtemperature and diluted with water. The resulting precipitate wascollected by filtration, washed with H₂O, and dried. Chromatography onsilica, eluting with CH₂Cl₂/MeOH (100:0 to 97:3), gave tert-butyl4-[2-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-8-oxo-7,8-dihydro-9H-purin-9-yl]-1-piperidinecarboxylate(176 mg, 69%): mp (CH₂Cl₂/i-Pr₂O) 269-272° C.; ¹H NMR (CDCl₃) δ 10.94(br s, 1H), 7.73 (dd, J=8.3, 0.3 Hz, 1H), 7.36 (t, J=8.2 Hz, 1H), 7.36(t, J_(HF)=53.6 Hz, 1H), 6.81 (d, J=7.8 Hz, 1H), 4.49 (tt, J=12.1, 4.1Hz, 1H), 4.38 (br s, 2H), 4.06 (s, 3H), 3.89 (dd, J=5.6, 3.6 Hz, 4H),3.82 (dd, J=5.6, 3.7 Hz, 4H), 2.85 (m, 2H), 2.56 (m, 2H), 1.83 (d,J=11.0 Hz, 2H), 1.48 (s, 9H); Anal. Calcd. for C₂₈H₃₄F₂N₈O₅.0.1 i-Pr₂O:C, 56.2; H, 5.8; N, 18.3. Found: C, 56.2; H, 5.90; N, 18.0%.

Reaction of the above carbamate (150 mg, 0.250 mmol) with an excess ofTFA (4 mL) in CH₂Cl₂ (40 mL) at room temperature for 2 hrs, followed bytreatment with aq. NH₃ gave2-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-9-(4-piperidinyl)-7,9-dihydro-8H-purin-8-one(96 mg, 77%), which was used in the next step without furtherpurification.

Powdered K₂CO₃ (217 mg, 1.57 mmol) was added to a sonicated suspensionof the above amine (87 mg, 0.174 mmol) in CH₂Cl₂ (50 mL). The mixturewas cooled to 0° C. and methanesulfonyl chloride (0.06 mL, 0.775 mmol)added dropwise. The reaction mixture was allowed to warm to roomtemperature and stirred for 5 hrs. Water was added, the phases wereseparated, and the aqueous phase was extracted with CH₂Cl₂ (1×). MeOHwas added to the combined organic extracts to dissolve the precipitate,the solution was dried (Na₂SO₄), and the solvents were removed.Recrystallization from CH₂Cl₂/MeOH gave2-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-9-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-7,9-dihydro-8H-purin-8-one(48 mg, 48%): mp 268-271° C.; ¹H NMR (CDCl₃) δ 11.08 (br s, 1H), 7.76(dd, J=8.4, 0.3 Hz, 1H), 7.40 (t, J=8.2 Hz, 1H), 7.37 (t, J_(HF)=53.6Hz, 1H), 6.83 (d, J=7.9 Hz, 1H), 4.50 (tt, J=11.8, 4.1 Hz, 1H),4.08-4.05 (m, 2H), 4.06 (s, 3H), 3.92 (m, 4H), 3.84 (m, 4H), 2.92-2.87(m, 2H), 2.88 (s, 3H), 2.79 (ddd, J=16.5, 12.3, 3.8 Hz, 2H), 1.96 (dd,J=11.7, 2.4 Hz, 2H); Anal. Calcd. for C₂₄H₂₈F₂N₈O₅S.0.48H₂O: C, 49.1; H,5.0; N, 19.1. Found: C, 49.1; H, 4.9; N, 19.0%.

Example 97 Synthesis of2-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-9-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-9H-purine

A mixture of tert-butyl4-{[5-amino-2-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-4-pyrimidinyl]amino}-1-piperidinecarboxylate(Example 96) (250 mg, 0.435 mmol), trimethylorthoformate (5 mL), andp-TSOH.H₂O (8.3 mg, 0.0436 mmol) was heated at 95-100° C. for 3 hrs. Themixture was cooled to room temperature and the solvent was removed undervacuum. Chromatography on silica, eluting with CH₂Cl₂/MeOH (100:0 to99:1), gave tert-butyl4-[2-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-9H-purin-9-yl]-1-piperidinecarboxylate(193 mg, 76%): mp (CH₂Cl₂/MeOH) 213-215° C.; ¹H NMR (CDCl₃) 7.82 (s,1H), 7.79 (d, J=8.3 Hz, 1H), 7.44 (t, J_(HF)=53.6 Hz, 1H), 7.35 (t,J=8.2 Hz, 1H), 6.81 (d, J=7.9 Hz, 1H), 4.57 (tt, J=12.0, 4.0 Hz, 1H),4.38 (m, 6H), 4.06 (s, 3H), 3.88 (t, J=4.9 Hz, 4H), 2.95 (t, J=12.6 Hz,2H), 2.19 (dd, J=12.1, 2.0 Hz, 2H), 2.05 (dq, J=12.3, 4.2 Hz, 2H), 1.49(s, 9H); Anal. Calcd. for C₂₈H₃₄F₂N₈O₄: C, 57.5; H, 5.9; N, 19.2. Found:C, 57.3; H, 5.8; N, 19.1%.

Reaction of the above carbamate (165 mg, 0.282 mmol) with an excess ofTFA (2 mL) in CH₂Cl₂ (10 mL) at room temperature for 1.5 hrs, followedby treatment with aq. NH₃ gave2-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-9-(4-piperidinyl)-9H-purine(121 mg, 88%), which was used in the next step without furtherpurification: ¹H NMR (CDCl₃) δ 7.87 (s, 1H), 7.81 (dd, J=8.4, 0.5 Hz,1H), 7.48 (t, J=53.6 Hz, 1H), 7.35 (t, J=8.2 Hz, 1H), 6.81 (d, J=7.8 Hz,1H), 4.54 (tt, J=12.0, 4.1 Hz, 1H), 4.38 (br s, 4H), 4.07 (s, 3H), 3.88(t, J=4.8 Hz, 4H), 3.30 (d, J=12.4 Hz, 2H), 2.86 (dt, J=12.4, 2.3 Hz,2H), 2.20 (dd, J=11.8, 2.2 Hz, 2H), 2.04 (dq, J=12.3, 4.1 Hz, 2H).

Methanesulfonyl chloride (0.08 mL, 1.03 mmol) was added dropwise to amixture of the above amine (102 mg, 0.211 mmol) and powdered K₂CO₃ (263mg, 1.90 mmol) in CH₂Cl₂ (10 mL) at 0° C. The mixture was allowed towarm to room temperature and was stirred for 5 hrs. Water was added, thephases were separated, and the aqueous phase was extracted with CH₂Cl₂.The combined organic extracts were dried (Na₂SO₄) and the solvent wasremoved under vacuum. Recrystallization from CH₂Cl₂/MeOH gave2-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-9-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-9H-purine(105 mg, 88%): mp 236-239° C.; ¹H NMR (CDCl₃) δ 7.84 (s, 1H), 7.76 (dd,J=8.4, 0.5 Hz, 1H), 7.42 (t, T_(HF)=53.6 Hz, 1H), 7.36 (t, J=8.2 Hz,1H), 6.81 (d, J=7.8 Hz, 1H), 4.57 (tt, J=11.7, 4.4 Hz, 1H), 4.38 (br s,4H), 4.09 (m, 2H), 4.06 (s, 3H), 3.88 (t, J=4.8 Hz, 4H), 2.96 (dt,J=12.5, 2.8 Hz, 2H), 2.88 (s, 3H), 2.35-2.20 (m, 4H); Anal. Calcd. forC₂₄H₂₈F₂N₈O₄S: C, 51.2; H, 5.0; N, 19.9. Found: C, 51.0; H, 4.9; N,19.7%.

Example 98 Synthesis of5-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-3-[1-(methylsulfonyl)-4-piperidinyl]-7-(4-morpholinyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine

Aqueous NaNO₂ solution (0.5 M, 1.7 mL) was added dropwise to a stirredsuspension of tert-butyl4-{[5-amino-2-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-4-pyrimidinyl]amino}-1-piperidinecarboxylate(Example 96) (250 mg, 0.435 mmol) in HOAc/H₂O (2:1, 12 mL) at 0° C. Thereaction mixture was stirred at 0° C. for 1.5 hrs and then diluted withH₂O. The resulting precipitate was collected by filtration, washedsequentially with H₂O and aqueous NH₃, and dried to give tert-butyl4-[5-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-7-(4-morpholinyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-1-piperidinecarboxylate(192 mg, 75%): mp (CH₂Cl₂/hexanes) 220-222° C.; ¹H NMR (CDCl₃) δ 7.81(dd, J=8.4, 0.6 Hz, 1H), 7.42 (t, J_(HF)=53.6 Hz, 1H), 7.38 (t, J=8.2Hz, 1H), 6.83 (d, J=7.71 Hz, 1H), 4.92 (tt, J=11.3, 4.1 Hz, 1H), 4.79(br s, 2H), 4.33 (m, 2H), 4.15 (br s, 2H), 3.92 (dd, J=13.4, 3.0 Hz,4H), 3.05 (t, J=12.0 Hz, 2H), 2.40 (dq, J=12.0, 4.4 Hz, 2H), 2.18 (dd,J=12.9, 2.5 Hz, 2H), 1.50 (s, 9H); Anal. Calcd. for C₂₇H₃₃F₂N₉O₄: C,55.4; H, 5.7; N, 21.5. Found: C, 55.5; H, 5.7; N, 21.3%.

Reaction of the above carbamate (158 mg, 0.270 mmol) with an excess ofTFA (2 mL) in CH₂Cl₂ (10 mL) at room temperature for 2 hrs, followed bytreatment with aq. NH₃ gave5-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-7-(4-morpholinyl)-3-(4-piperidinyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine(112 mg, 85%), which was used in the next step without furtherpurification: ¹H NMR (CDCl₃) δ 7.83 (dd, J=8.4, 0.4 Hz, 1H), 7.46 (t,J_(HF)=53.6 Hz, 1H), 7.38 (t, J=8.2 Hz, 1H), 6.83 (d, J=7.9 Hz, 1H),4.87 (tt, J=11.7, 4.2 Hz, 1H), 4.80 (br s, 2H), 4.15 (br s, 2H), 4.07(s, 3H), 3.92 (d, J=15.0 Hz, 4H), 3.34 (m, 2H), 2.88 (dt, J=12.7, 2.5Hz, 2H), 2.38 (dq, J=12.0, 4.2 Hz, 2H), 2.18 (m, 2H).

Methanesulfonyl chloride (0.09 mL, 1.16 mmol) was added dropwise to amixture of the above amine (107 mg, 0.220 mmol) and powdered K₂CO₃ (274mg, 1.98 mmol) in CH₂Cl₂ (10 mL) at 0° C. The mixture was allowed towarm to room temperature and was stirred for 16.5 hrs. Water was added,the phases were separated, and the aqueous phase was extracted withCH₂Cl₂ (1×). The combined organic extracts were dried (Na₂SO₄) and thesolvent removed under vacuum. Recrystallization from CH₂Cl₂/MeOH gave5-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-3-[1-(methylsulfonyl)-4-piperidinyl]-7-(4-morpholinyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine(108 mg, 87%): mp 258-259° C.; ¹H NMR (CDCl₃) δ 7.81 (dd, J=8.4, 0.5 Hz,1H), 7.41 (t, J_(HF)=53.5 Hz, 1H), 7.39 (t, J=8.2 Hz, 1H), 6.84 (d,J=7.7 Hz, 1H), 4.93 (tt, J=10.5, 4.2 Hz, 1H), 4.79 (br s, 2H), 4.16 (brs, 2H), 4.07 (s, 3H), 4.01-3.90 (m, 6H), 3.14 (m, 2H), 2.89 (s, 3H),2.60 (m, 2H), 2.35 (m, 2H); Anal. Calcd. for C₂₃H₂₇F₂N₉O₄S: C, 49.0; H,4.8; N, 22.4. Found: C, 48.9; H, 4.8; N, 22.2%.

Example 99 Synthesis ofN-[2-({4-[6-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-4-(4-morpholinyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl}sulfonyl)ethyl]-N,N-dimethylamine

A mixture of 0.41 g (0.84 mmol) of6-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-4-(4-morpholinyl)-1-(4-piperidinyl)-1H-pyrazolo[3,4-d]pyrimidine(Example 8) and 0.27 g (2 mmol) DIPEA in CH₂Cl₂ was cooled to −15° C.,and 200 mg (1.2 mmol) of 2-chloroethanesulfonyl chloride was added. Themixture was allowed to warm to 0° C. over 1 hr, and water was added. Theorganic layer was dried and concentrated. Chromatography on silica,eluting with CH₂Cl₂/EtOAc (1:1), gave 216 mg (45% yield) of6-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-4-(4-morpholinyl)-1-[1-(vinylsulfonyl)-4-piperidinyl]-1H-pyrazolo[3,4-d]pyrimidine:mp (CH₂Cl₂-MeOH) 243-246° C.; ¹H NMR (CDCl₃) δ 8.00 (s, 1H), 7.81 (dd,J=8.4, 0.7 Hz, 1H), 7.44 (t, J_(HF)=53.5 Hz, 1H), 7.37 (t, J=8.2 Hz,1H), 6.82 (d, J=7.7 Hz, 1H), 6.51 (dd, J=16.6, 9.9 Hz, 1H), 6.29 (d,J=16.6 Hz, 1H), 6.07 (d, J=9.9 Hz, 1H), 4.81 (tt, J=11.2, 4.1 Hz, 1H),4.07 (s, 3H), 4.06 (m, 4H), 3.96 (m, 1H), 3.91 (m, 4H), 3.88 (m, 1H),2.95 (dt J=12.4, 2.6 Hz, 2H), 2.43 (ddd, J=24.5, 11.8, 4.2 Hz, 2H), 2.14(dd, J=11.8, 4.2 Hz, 2H); Anal. Calcd. for C₂₅H₂₈F₂N₈O₄S: C, 52.3; H,4.9; N, 19.5. Found: C, 52.3; H, 4.7; N, 19.8%.

A suspension of the above vinylsulfonamide (140 mg, 0.243 mmol) in 100mL THF was treated with 10 mL of 40% aq. dimethylamine to give a clearsolution. After 10 min, the mixture was diluted with water and the THFwas removed under vacuum to give 140 mg (93% yield) ofN-[2-({4-[6-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-4-(4-morpholinyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl}sulfonyl)ethyl]-N,N-dimethylamineas a white solid: ¹H NMR (CDCl₃) δ 7.99 (s, 1H), 7.82 (dd, J=8.4, 0.6Hz, 1H), 7.45 (t, J_(HF)=53.6 Hz, 1H), 7.37 (t, J=8.2 Hz, 1H), 6.83 (d,J=7.8 Hz, 1H), 4.85 (tt, J=11.1, 4.1 Hz, 1H), 4.07 (s, 3H), 4.06 (m,4H), 4.02 (m, 1H), 3.98 (m, 1H), 3.91 (m, 4H), 3.18-3.07 (m, 4H), 2.80(dd, J=8.3, 6.4 Hz, 2H), 2.41 (dq, J=11.7, 4.2 Hz, 2H), 2.29 (s, 6H),2.14 (dd, J=12.5, 2.5 Hz, 2H).

Dimethanesulfonate: mp (MeOH-EtOAc) 191-193° C.; ¹H NMR (DMSO-d₆) δ 9.53(br, 1H, exchangeable with D₂O), 8.46 (s, 1H), 7.88 (d, J=7.9 Hz, 1H),7.78 (t, J_(HF)=52.9 Hz, 1H), 7.40 (t, J=8.2 Hz, 1H), 6.95 (d, J=7.7 Hz,1H), 4.91 (ddd, J=15.5, 10.9, 4.5 Hz, 1H), 4.01 (m, 4H), 4.00 (s, 3H),3.83 (m, 6H), 3.64 (dd, J=10.0, 5.5 Hz, 2H), 3.49 (m, 1H), 3.21 (dt,J=12.3, 2.7 Hz, 2H), 2.87 (d, J=4.1 Hz, 6H), 2.25-2.09 (m, 4H); Anal.Calcd. for C₂₉H₄₃F₂N₉O₁₀S₃: C, 42.9; H, 5.3; N, 15.5. Found: C, 42.8; H,5.55; N, 15.5%.

Example 100 Synthesis ofN-(5-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}-2-pyridinyl)methanesulfonamide

To 0.652 g (4.69 mmol) of 2-amino-5-nitropyridine in THF (5 mL) wasadded 3.5 mL of NaHMDS (2M solution in THF) at 0° C. After 20 min asolution of 1.085 g (4.97 mmol) of di-tert-butyl dicarbonate in THF (6mL) was added and the mixture was slowly warmed to room temperatureovernight. Water was added, and the mixture was extracted with EtOAc(×4). The organic layer was washed with brine, dried (Na₂SO₄), andconcentrated. Chromatography on, silica with hexanes-EtOAc (7:3), gave0.695 g (62% yield) of tert-butyl-5-nitropyridin-2-ylcarbamate as anorange powder: ¹H NMR (CDCl₃) 89.19 (dd, J=2.8, 0.5 Hz, 1H), 8.93 (br s,1H), 8.46 (ddd, J=9.4, 2.8, 0.5 Hz, 1H), 8.20 (dd, J=9.5, 0.5 Hz, 1H),1.59 (s, 9H); LCMS (APCI⁻) m/z: 238 (MH⁺, 100%).

To 0.314 g (1.31 mmol) of the above nitro compound in THF-MeOH (16 mL,1:1) was added 0.460 g of 10% Pd/C and the mixture was stirred underhydrogen (40 in/Hg) for 4 hrs. The reaction mixture was filtered throughcelite, washed with MeOH and concentrated to give 0.277 g (99% yield) oftert-butyl 5-aminopyridin-2-yl-carbamate as a white powder: ¹H NMR(DMSO-d₆) δ9.00 (br s, 1H), 7.62 (dd, J=2.7, 0.4 Hz, 1H), 7.39 (d, J=8.7Hz, 1H), 6.94 (dd, J=8.7, 2.8 Hz, 1H), 4.92 (s, 2H), 1.44 (s, 9H).

To 0.277 g (1.33 mmol) of the above amino compound in THF (3 mL) wasadded 0.61 mL of n-butyllithium (2.5 M solution in hexanes) and themixture was stirred for 10 min. A solution of 0.176 g (0.44 mmol) of1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazolein THF (5 mL) was added and the resulting mixture was stirred for 1 hrat room temperature. The reaction mixture was neutralized with aceticacid, diluted with water, and extracted with EtOAc. The organic layerwas washed with water and aq. NH₃, dried, and concentrated.Chromatography on silica, eluting with hexanes-EtOAc (7:3), then withCH₂Cl₂-EtOAc (3:1), gave 0.033 g (13% yield) of tert-butyl5-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}-2-pyridinylcarbamate:¹H NMR (DMSO-d₆) δ 10.02 (s, 1H), 9.66 (s, 1H), 8.54 (s, 1H), 8.17-7.80(m, 4H), 7.39 (d, J=8.7 Hz, 1H), 6.97-6.93 (m, 1H), 3.98 (s, 3H), 3.82(s, 4H), 3.74-3.72 (m, 4H), 1.48 (s, 9H).

To 0.033 g (0.06 mmol) of the above carbamate in CH₂Cl₂ (3 mL) was added0.1 mL (1.30 mmol) of trifluoroacetic acid, and the mixture was stirredfor 5 hrs. The reaction mixture was diluted with CH₂Cl₂ and aq. NH₄OH,and the organic layer was washed with brine, dried (Na₂SO₄), andconcentrated. The residue was recrystallized from EtOH/CH₂Cl₂ to give0.0133 g (49% yield) ofN⁵-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2,5-pyridinediamine,as a brown powder: mp 267-270° C.; ¹H NMR (DMSO-d₆) δ 9.67-9.49 (m, 1H),8.18-7.27 (m, 5H), 6.96 (d, J=7.6 Hz, 1H), 6.48 (d, J=8.4 Hz, 1H),5.87-5.75 (m, 2H), 3.98 (s, 3H), 3.81 (s, 4H), 3.71 (s, 4H); HRMS (ESI)M+H⁺ Calcd. for C₂₁H₂₂F₂N₉O₂: m/z 470.1859. Found: m/z 470.1867.

To 86 mg (0.18 mmol) of the above amine in pyridine (1 mL) was added 17μL (0.22 mmol) of methanesulfonyl chloride, and the mixture was heatedat 50° C. for 18 hrs. The mixture was cooled to room temperature, sat.NaHCO₃ solution was added, and the resulting mixture was extracted withEtOAc (×4). The combined organic layers were dried, and the solventremoved. Chromatography on silica, eluting with CH₂CH₂/EtOAc (1:1) gave50 mg (51% yield) ofN-(5-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}-2-pyridinyl)methanesulfonamide,as a yellow powder: mp 302-306° C.; ¹H NMR (DMSO-d₆) δ 10.49 (s, 1H),10.04 (s, 1H), 8.56 (s, 1H), 8.16-7.41 (m, 4H), 7.05 (d, J=8.8 Hz, 1H),6.96 (d, J=8.0 Hz, 1H), 3.98 (s, 3H), 3.82 (s, 4H), 3.74-3.72 (m, 4H),3.29 (s, 3H); HRMS (ESI) M+Na⁺ Calcd. for C₂₃H₂₃F₂N₉NaO₄S: m/z 570.1454;Found: m/z 570.1442.

Example 101 Synthesis ofN-(5-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}-2-pyridinyl)-N-methylmethanesulfonamide

To 0.652 g (4.69 mmol) of 2-amino-5-nitropyridine in THF (5 mL) wasadded 3.5 mL of NaHMDS (2M solution in THF) at 0° C. After 20 min, asolution of 1.085 g (4.97 mmol) of di-tert-butyl dicarbonate in THF (6mL) was added, and the mixture was slowly warmed to room temperatureovernight. Water was added, and the mixture was extracted with EtOAc(×4). The combined organic layers were washed with brine, dried(Na₂SO₄), and concentrated. Purification by flash column chromatographyon silica, eluting with hexanes-EtOAc (7:3), gave 0.695 g (62% yield) oftert-butyl 5-nitro-2-pyridinylcarbamate as an orange powder: ¹H NMR(CDCl₃) δ 9.19 (dd, J=2.8, 0.5 Hz, 1H), 8.93 (br s, 1H), 8.46 (ddd,J=9.4, 2.8, 0.5 Hz, 1H), 8.20 (dd, J=9.5, 0.5 Hz, 1H), 1.59 (s, 9H);LCMS (APCI⁻) m/z: 238 (MH⁺, 100%).

To 0.378 g (1.58 mmol) of the above nitro compound in DMF (6 mL) at 0°C. was added 0.067 g (2.80 mmol) of sodium hydride. After 20 min, 0.12mL (1.93 mmol) of methyl iodide was added, and the mixture was stirredfor 2 hrs. Water was added, and the mixture was extracted with EtOAc(×4). The combined organic layer was washed successively with 1M HCl,sat. NaHCO₃ solution, and brine, dried (Na₂SO₄), and concentrated, togive 0.40 g (99% yield) of tert-butylmethyl(5-nitro-2-pyridinyl)carbamate: ¹H NMR (CDCl₃) δ 9.19 (d, J=2.7Hz, 1H), 8.36 (dd, J=9.4, 2.7 Hz, 1H), 8.14 (dd, J=9.4, 0.3 Hz, 1H),3.50 (s, 3H), 1.57 (s, 9H); LCMS (APCI⁻) m/z: 253 (MH⁺, 100%).

To 0.40 g (1.58 mmol) of the above nitro compound in MeOH (25 mL) wasadded 0.4 g of 10% Pd/C and the mixture was stirred under hydrogen (40in Hg) for 4 hrs. After filtration through celite the reaction mixturewas concentrated, to give 0.36 g (97% yield) of tert-butyl5-amino-2-pyridin-2-yl(methyl)carbamate, as a yellow oil: ¹H NMR(DMSO-d₆) δ 7.70 (dd, J=2.9, 0.5 Hz, 1H), 7.07 (d, J=8.6 Hz, 1H), 6.93(dd, J=8.6, 2.9 Hz, 1H), 3.12 (s, 3H), 1.39 (s, 9H).

To 0.356 g (1.53 mmol) of the above amine in THF (3 mL) was added 0.70mL of n-butyllithium (2.5 M solution in hexanes) and the mixture wasstirred for 10 min. A solution of 0.21 g (0.52 mmol) of1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazolein THF (5 mL) was added, and the resulting mixture was stirred for 1 hr.The reaction mixture was neutralized with acetic acid, diluted withwater, and extracted with EtOAc. The organic layer was washed with waterand aq. NH₃, and dried. The solvent was removed under vacuum, and theproduct mixture was purified by flash column chromatography, elutingwith CH₂Cl₂/EtOAc (3:1), to give 0.075 g (13% yield) of tert-butyl5-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}-2-pyridinyl(methyl)carbamate,as a yellow powder: ¹H NMR (DMSO-d₆) δ 10.11 (s, 1H), 8.68-7.41 (m, 5H),7.61 (d, J=9.0 Hz, 1H), 6.97 (d, J=8.1 Hz, 1H), 3.98 (s, 3H), 3.83 (s,4H), 3.74-3.73 (m, 4H), 3.29 (s, 3H), 1.47 (s, 9H); LCMS (APCI⁺) m/z:585 (MH⁺, 100%).

To 0.0750 g (0.13 mmol) of the above carbamate in CH₂Cl₂ (3 mL) wasadded 0.1 mL (1.30 mmol) of trifluoroacetic acid and the mixture wasstirred for 5 hrs. After dilution with CH₂Cl₂, the mixture was treatedwith H₂O and aq. NH₃, and the organic layer was washed with brine, dried(Na₂SO₄), and concentrated. The residue was recrystallized fromEtOH/CH₂Cl₂ to give 0.0472 g (75% yield) ofN⁵-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N²-methyl-2,5-pyridinediamine:mp 218-221° C.; ¹H NMR (CDCl₃) δ8.31-7.73 (m, 2H), 7.62 (dd, J=8.8, 2.6Hz, 1H), 7.56-7.31 (m, 2H), 6.82-6.80 (m, 2H), 6.46 (d, J=8.8 Hz, 1H),4.76 (br s, 1H), 4.04 (s, 3H), 3.89 (s, 4H), 3.79 (s, 4H), 2.96 (s, 3H);HRMS (ESI) M+H⁺ Calcd. for C₂₂H₂₄F₂N₉O₂: m/z 484.2016. Found: m/z484.2023.

To 30 mg (0.06 mmol) of the above methylamine in CH₂Cl₂ (2 mL) at 0° C.was added 0.01 mL (0.07 mmol) of Et₃N, and after 10 min 5 μL (0.06 mmol)of methanesulfonyl chloride was added, and the mixture was stirred for 1hr. Water was added, and the mixture was extracted with EtOAc. Theorganic layer washed with brine, dried, and the solvent was removed.Chromatography on silica, eluting first with hexanes/EtOAc (1:1) thenwith CH₂Cl₂/EtOAc (1:1), gave 0.019 g (55% yield) ofN-(5-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}-2-pyridinyl)-N-methylmethanesulfonamide,as a white powder: mp 250-253° C.; ¹H NMR (CDCl₃) δ8.61 (s, broad, 1H),8.11-7.25 (m, 6H), 6.81 (d, J=8.0 Hz, 1H), 4.02 (s, 3H), 3.91 (s, 4H),3.82-3.80 (m, 4H), 3.41 (s, 3H), 3.01 (s, 3H); HRMS (ESI) M+H⁺ Calcd.for C₂₃H₂₆F₂N₉O₄S: m/z 562.1791. Found: m/z 562.1785.

Example 102 Biological Activity

A. Inhibition of Isolated Enzyme

Compounds were evaluated for their ability to inhibit Class I PI3-kinase enzymes p110δ/p85, p110α/p85, and p110β/p85. Reaction mixturescomprising 0.1 μg of a recombinant enzyme, 10 μg ofL-α-phosphatidylinositol, and 2× Lipid Kinase Buffer (40 mM Tris-HCl, pH7.4, 200 mM NaCl, 1 mM EDTA), which contains either DMSO only as acontrol or the test compound in DMSO (the final DMSO concentration is1%), were activated by the addition of an ATP mix (5 mM MgCl₂, 100 μMATP, and 0.1 μL [γ³³P]ATP). Reactions were incubated at room temperaturefor 1 hr, and then stopped by the addition of 1M HCl. The lipids werethen extracted using a two step procedure. Firstly, 200 μL ofchloroform/methanol (1:1) was added, the biphasic reactions mixed andcentrifuged briefly, and the inorganic phase was removed and discarded.Following this, 80 μL of methanol:HCl (1:1) was added and the sameprocedure followed. The organic phase (70 μL) was then transferred to aclean 1.6 mL tube and the reactions were dried using a Speedvac, with noheating, for 30 mM. The reactions were spotted onto TLC plates (MerckLtd) and developed for 1 hr in propanol-1:2 M acetic acid (13:7). TheTLC plates were then dried at room temperature and quantified using aphosphorimager (StormImager, Amersham). Nine compound concentrationswere used for each test compound to determine its IC₅₀ value. Eachexperiment was performed twice and the average IC₅₀ value is usedherein. The results are summarized in Table 1.

B. Cellular Growth Inhibition.

The compounds were evaluated against two early passage human cell linesNZB5 and NZOV9 (Marshall et al., Oncol. Res. 2004, 14, 297). The cellswere grown in ITS medium (α-modified minimal essential mediumsupplemented insulin, transferrin, selenite, and 5% fetal bovine serum)and grown on 96-well tissue culture plates under an atmosphere of 5% O₂,5% CO₂, and 90% N₂. Individual wells contained 500-1,000 cells(depending on the growth rate) in a volume of 150 μL. Compounds wereadded at 10-fold concentration steps to a maximum of 20 μM and plateswere incubated for five days, with ³H-thymidine being added over thelast 6 hrs. Cells were harvested and incorporated radioactivitymeasured. Duplicate samples were analyzed for each compound dose withmultiple control samples. Data were fitted by a least-squares method toan exponential of the form y=y₀+ae^(−bx), where y is the radioactivity(corrected for background and normalized to 100% of the control), x isthe radiation dose, and y₀, a, and b are variables, and the IC₅₀ valuedefined as the compound concentration reducing ³H-thymidine levels by50%. The results are summarized in Table 1.

TABLE 1 Biological Activity Enzyme IC₅₀* Cell IC₅₀* Example p110α p110βp110δ NZB5 NZOV9 1 B A A C B 2 A B A B B 3 A A A B A 4 B B B B B 5 A A AB A 6 A A A B A 7 B C B B B 8 A B A B A 9 A B A A A 10 A B A B A 11 A CA B B 12 A B A B B 13 A B A B A 14 A A A B A 15 A B A B A 16 A A C B 17A A A B A 18 A B A B A 19 B B A B B 20 A B A A A 21 A B A B B 22 A B A BA 23 A A A B A 24 B C A 25 A 26 B 27 A 28 A 29 A 30 A 31 A 32 A B A 33 AA A 34 A B A 35 A A A 36 A B A 37 A B A 38 A B A 39 A B A 40 A B A 41 A42 A B A 43 A 44 A B A 45 A A B A 46 A B A 47 A A B A 48 A A 49 A A 50 AA B B 51 A A C B 52 C C 53 B A C B 54 B A B A 55 A A 56 A A 58 A A 59 BC A 61 A A 63 B C B B B 64 A B B B A 65 A B B B B 66 A C B B B 67 A C BB B 68 A C B B A 69 A C A B A 70 A C A A A 71 A C A A A 72 A B 73 B B 74A B 75 B B 76 B B 77 B B 78 A C B B A 79 A C B B A 80 A A 81 A A 82 A A83 B B 84 A B A A C 85 B C B B 86 B C 87 A B 88 A B 89 A B C B 90 A C BB A 91 A C B A A 92 A B B B B 93 A A 94 B B 95 B C 96 A B 97 A A 98 A B99 A B B A A 100 A A B A 101 A B A A A *A. < 0.1 μM; B. 0.1-1.0 μM; C. >1.0 μM

Example 103 Pharmacological Stability

Pharmacological stability of2-(difluoromethyl)-1-[4-[4-(methylsulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole(“the sulfonamide,” Example 1) and1-[4-(4-acetyl-1-piperazinyl)-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole(“the carboxamide,” EP 1864665 and WO 2006/095906) were incubated inhuman plasma at 37° C. for 20 hrs. The sulfonamide displayed a greaterthan five-fold increase in stability compared to the carboxamide.

The examples set forth above are provided to give those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the claimed embodiments, and are not intended to limit thescope of what is disclosed herein. Modifications that are obvious topersons of skill in the art are intended to be within the scope of thefollowing claims. All publications, patents, and patent applicationscited in this specification are incorporated herein by reference as ifeach such publication, patent or patent application were specificallyand individually indicated to be incorporated herein by reference.

What is claimed is:
 1. A compound of Formula IA:

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof; or a pharmaceutically acceptable salt, or prodrugthereof; wherein: R¹ and R² are each independently (a) hydrogen, cyano,halo, or nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or(c) —C(O)R^(1a), —C(O)OR^(1b), —C(O)NR^(1b)R^(1c),—C(NR^(a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),—OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); wherein each R^(1a), R^(1b),R^(1c), and R^(1d) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl; or (iii) R^(1b) and R^(1c) together withthe N atom to which they are attached form heterocyclyl; R³ and R⁴ areeach independently hydrogen or C₁₋₆ alkyl; or R³ and R⁴ are linkedtogether to form a bond, C₁₋₆ alkylene, C₁₋₆ heteroalkylene, C₂₋₆alkenylene, or C₂₋₆ heteroalkenylene; R⁵ is independently C₁₋₆ alkyl orC₂₋₆ alkenyl, each optionally substituted with one or more substituents,each of which is independently selected from the group consisting ofheterocyclyl and —NR^(f)R^(g); or R⁵ is —NR^(5m)R^(5n), where R^(5m) andR^(5n) are each independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, orheterocyclyl; R⁶ is independently hydrogen or C₁₋₆ alkyl; Q is C₁₋₆alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene, C₃₋₇ cycloalkylene, C₆₋₁₄arylene, heteroarylene, or heterocyclylene; T¹ is independently a bond,C₁₋₆ alkylene, —O—, or —NR⁸—; T² is independently a bond, C₁₋₆ alkylene,or —NR⁸—; wherein each R⁸ is independently hydrogen, C₁₋₆ alkyl, C₂₋₆alkenyl, or C₂₋₆ alkynyl; and with the proviso that at least one of thetwo atoms that are directly attached to the —SO₂— group is nitrogen; X,Y, and Z are each independently a nitrogen atom or CR⁹, with the provisothat at least two of X, Y, and Z are nitrogen atoms; where R⁹ ishydrogen or C₁₋₆ alkyl; wherein each alkyl, alkylene, heteroalkylene,alkenyl, alkenylene, heteroalkenylene, alkynyl, alkynylene, cycloalkyl,cycloalkylene, aryl, arylene, heteroaryl, heteroarylene, heterocyclyl,and heterocyclylene in R¹, R², R³, R⁴, R⁶, R⁸, R⁹, R^(1a), R^(1b),R^(1c), R^(1d), R^(5m), R^(5n), Q, T¹, and T², is optionally substitutedwith one or more groups, each independently selected from (a) cyano,halo, and nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, and heterocyclyl,each optionally substituted with one or more, in one embodiment, one,two, three, or four, substituents Q¹; and (c) —C(O)R^(a), —C(O)OR^(a),—C(O)NR^(b)R^(c), —C(NR^(a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a),—OC(O)OR^(a), —OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a),—OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c), —NR^(b)R^(c), —NR^(a)C(O)R^(d),—NR^(a)C(O)OR^(d), —NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c),—NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c),—NR^(a)S(O)₂NR^(b)R^(c), —SR^(a), —S(O)R^(a), —S(O)₂R^(a),—S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c), wherein each R^(a), R^(b),R^(c), and R^(d) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl, each optionally substituted with one ormore substituents Q¹; or (iii) R^(b) and R^(c) together with the N atomto which they are attached form heterocyclyl, optionally substitutedwith one or more substituents Q¹; wherein each Q¹ is independentlyselected from the group consisting of (a) cyano, halo, and nitro; (b)C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl,C₇₋₁₅ aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R^(e),—C(O)OR^(e), —C(O)NR^(f)R^(g), —C(NR^(e))NR^(f)R^(g), —OR^(e),—OC(O)R^(e), —OC(O)OR^(e), —OC(O)NR^(f)R^(g), —OC(═NR^(e))NR^(f)R^(g),—OS(O)R^(e), —OS(O)₂R^(e), —OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g),—NR^(f)R^(g), —NR^(e)C(O)R^(h), —NR^(e)C(O)OR^(h),—NR^(e)C(O)NR^(f)R^(g), —NR^(e)C(═NR^(h))NR^(f)R^(g), —NR^(e)S(O)R^(h),—NR^(e)S(O)₂R^(h), —NR^(e)S(O)NR^(f)R^(g), —NR^(e)S(O)₂NR^(f)R^(g),—SR^(e), —S(O)R^(e), —S(O)₂R^(e), —S(O)NR^(f)R^(g), and—S(O)₂NR^(f)R^(g); wherein each R^(e), R^(f), R^(g), and R^(h) isindependently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl;or (iii) R^(f) and R^(g) together with the N atom to which they areattached form heterocyclyl.
 2. The compound of claim 1, having thestructure of Formula Ia:


3. The compound of claim 1, having the structure of Formula II:


4. The compound of claim 1, wherein R¹ is independently hydrogen or—OR^(1a), where R^(1a) is C₁₋₆ alkyl, optionally substituted with—NR^(f)R^(g); and R^(f) and R^(g) are each independently hydrogen orC₁₋₆ alkyl.
 5. The compound of claim 4, wherein R¹ is hydrogen, methoxy,or dimethylaminopropoxy.
 6. The compound of claim 1, wherein R² isindependently hydrogen, C₁₋₆ alkyl, or —NR^(1b)R^(1c); where R^(1b) andR^(1c) are each independently (a) hydrogen; or (b) C₁₋₆ alkyl, C₂₋₆alkenyl, or C₂₋₆ alkynyl, each optionally substituted with one or moresubstituents, where each substituent is independently —OR^(e) or—NR^(f)R^(g).
 7. The compound of claim 6, wherein R² is independentlyhydrogen or amino.
 8. The compound of claim 1, wherein R³ and R⁴ areeach independently hydrogen or C₁₋₆ alkyl, optionally substituted withone or more groups.
 9. The compound of claim 8, wherein R³ and R⁴ arehydrogen.
 10. The compound of claim 1, wherein R⁵ is independently—(CR^(5a)R^(5b))_(m)—R^(5c), where R^(5a) and R^(5b) are eachindependently (a) hydrogen, cyano, or nitro; or (b) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl; each optionally substituted with one ormore substituents; R^(5c) is hydrogen, —NR^(5d)R^(5e), or heterocyclyl;R^(5d) and R^(5e) are each independently hydrogen or C₁₋₆ alkyl; and mis an integer of 0, 1, 2, or 3; and where each alkyl and heterocyclyl isindependently, optionally substituted with one or more groups.
 11. Thecompound of claim 10, wherein R^(5c) is hydrogen.
 12. The compound ofclaim 10, wherein R^(5b) is hydrogen.
 13. The compound of claim 10,wherein R^(5c) is hydrogen.
 14. The compound of claim 10, wherein R^(5c)is —NR^(5d)R^(5e), and R^(5d) and R^(5e) are each independently hydrogenor C₁₋₆ alkyl, optionally substituted with one or more groups.
 15. Thecompound of claim 14, wherein R^(5d) is hydrogen or methyl.
 16. Thecompound of claim 14, wherein R^(5e) is hydrogen or methyl.
 17. Thecompound of claim 10, wherein R^(5c) is amino, methylamino, ordimethylamino.
 18. The compound of claim 10, wherein m is 1, 2, or 3.19. The compound of claim 1, wherein R⁵ is independently methyl,ethenyl, dimethylaminomethyl, dimethylaminoethyl, ordimethylaminopropyl.
 20. The compound of claim 1, wherein R⁶ isindependently C₁₋₆ alkyl, optionally substituted with one to three halo.21. The compound of claim 20, wherein R⁶ is independently methyl,fluoromethyl, difluoromethyl, or trifluoromethyl.
 22. The compound ofclaim 1, wherein Q is independently C₃₋₇ cycloalkylene, C₆₋₁₄ arylene,heteroarylene, or heterocyclene.
 23. The compound of claim 22, wherein Qis independently cyclopropylene, cyclobutylene, cyclopentylene,cyclohexylene, phenylene, azetidinylene, pyrrolidinylene,piperidinylene, piperazinylene, pyrrolylene, thiazolylylene,pyrazolylene, or pyridylene.
 24. The compound of claim 22, wherein Q isindependently 1,3-azetidinylene, 1,3-pyrrolidinylene,1,3-piperidinylene, 1,4-piperidinylene, or 1,4-piperazinylene.
 25. Thecompound of claim 1, wherein T¹ is independently a bond or methylene.26. The compound of claim 1, wherein T² is independently —NR⁸—.
 27. Thecompound of claim 26, wherein R⁸ is independently hydrogen or C₁₋₆alkyl.
 28. The compound of claim 27, wherein R⁸ is independentlyhydrogen or methyl.
 29. The compound of claim 1 selected from the groupconsisting of:2-(difluoromethyl)-1-[4-[4-(methylsulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole;2-(difluoromethyl)-4-methoxy-1-[4-[4-(methylsulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole;2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(vinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole;({4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)-N,N-dimethylmethylamine;N-[2-({4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)ethyl]-N,N-dimethylamine;N-[3-({4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)propyl]-N,N-dimethylamine;2-(difluoromethyl)-4-methoxy-1-(4-(4-morpholinyl)-6-{4-[(4-morpholinylmethyl)sulfonyl]-1-piperazinyl}-1,3,5-triazin-2-yl)-1H-benzimidazole;2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[2-(4-morpholinyl)ethyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole;2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[3-(4-morpholinyl)propyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole;N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}methanesulfonamide;N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}-N-methylmethanesulfonamide;N-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N-[1-(methylsulfonyl)-4-piperidinyl]amine;N-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N-methyl-N-[1-(methylsulfonyl)-4-piperidinyl]amine;2-(difluoromethyl)-4-methoxy-1-[4-[4-(methylsulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazol-6-ylamine;2-(difluoromethyl)-4-methoxy-1-[4-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole;N-[2-({4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperidinyl}sulfonyl)ethyl]-N,N-dimethylamine;2-(difluoromethyl)-4-methoxy-1-[4-[1-(methylsulfonyl)-3-piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole;2-(difluoromethyl)-4-methoxy-[4-{[1-(methylsulfonyl)-4-piperidinyl]oxy}-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole;N¹-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N³,N³-dimethyl-N¹-[1-(methylsulfonyl)-3-piperidinyl]-1,3-propanediamine;4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[1-(methylsulfonyl)-3-piperidinyl]-6-(4-morpholinyl)-N-[3-(4-morpholinyl)propyl]-1,3,5-triazin-2-amine;N¹-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N³,N³-dimethyl-N¹-[1-(methylsulfonyl)-4-piperidinyl]-1,3-propanediamine;4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-N-[3-(4-morpholinyl)propyl]-1,3,5-triazin-2-amine;4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-{3-[4-(methylsulfonyl)-1-piperazinyl]propyl}-N-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine;N-{(3S)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]piperidinyl}-N-[3-(dimethylamino)propyl]methane-sulfonamide;N-[2-({4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)ethyl]-N,N-diethylamine;2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[2-(1-piperidinyl)ethyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole;N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}-2-(dimethylamino)ethanesulfonamide;N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}-2-(dimethylamino)-N-methylethanesulfonamide;N-{4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]phenyl}-2-(dimethylamino)ethanesulfonamide;N-{4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]phenyl}-2-(dimethylamino)-N-methylethanesulfonamide;N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-azetidinyl}-2-(dimethylamino)ethanesulfonamide;N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-azetidinyl}-2-(dimethylamino)-N-methylethanesulfonamide;trans-N-(4-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}cyclohexyl)methanesulfonamide;cis-N-(4-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}cyclohexyl)methanesulfonamide;N-[2-({4-[4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)ethyl]-N,N-dimethylamine;N-[2-({4-[4-[6-amino-2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)ethyl]-N,N-dimethylamine;2-(difluoromethyl)-4-methoxy-1-{4-[4-(methylsulfonyl)-1-piperazinyl]-6-tetrahydro-2H-pyran-4-yl-1,3,5-triazin-2-yl}-1H-benzimidazole;4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N,N-dimethyl-1-piperazinesulfonamide;1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N,N-dimethyl-4-piperidinesulfonamide;1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N-methyl-4-piperidinesulfonamide;1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N-[2-(dimethylamino)ethyl]-4-piperidinesulfonamide;1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N-methyl-3-pyrrolidinesulfonamide;1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N-[2-(dimethylamino)ethyl]-3-pyrrolidinesulfonamide;N-(5-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}-2-pyridinyl)methanesulfonamide;N-(5-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}-2-pyridinyl)-N-methylmethanesulfonamide;4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine;3-{4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-[4-(methylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-8-oxa-3-azabicyclo[3.2.1]octane;2-(difluoromethyl)-4-methoxy-1-[4-[4-(methylsulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-2-pyrimidinyl]-1H-benzimidazole;4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[1-(methylsulfonyl)-3-azetidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine;4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-methyl-N-[1-(methylsulfonyl)-3-azetidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine;N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-azetidinyl}methanesulfonamide;N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-azetidinyl}-N-methylmethanesulfonamide;4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[(3R)-1-(methylsulfonyl)pyrrolidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine;4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-methyl-N-[(3R)-1-(methylsulfonyl)pyrrolidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine;4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[(3S)-1-(methylsulfonyl)pyrrolidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine;4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-methyl-N-[(3S)-1-(methylsulfonyl)pyrrolidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine;N-{(3R)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]pyrrolidinyl}methanesulfonamide;N-{(3R)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]pyrrolidinyl}-N-methylmethanesulfonamide;N-{(3S)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]pyrrolidinyl}methanesulfonamide;N-{(3S)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]pyrrolidinyl}-N-methylmethanesulfonamide;4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[(3R)-1-(methylsulfonyl)piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine;4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-methyl-N-[(3R)-1-(methylsulfonyl)piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine;4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[(3S)-1-(methylsulfonyl)piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine;4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-methyl-N-[(3S)-1-(methylsulfonyl)piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine;N-{(3R)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]piperidinyl}methanesulfonamide;N-{(3R)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]piperidinyl}-N-methylmethanesulfonamide;N-{(3S)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]piperidinyl}methanesulfonamide;N-{(3S)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]piperidinyl}-N-methylmethanesulfonamide;N-{2-[(4-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]oxy}-1-piperidinyl)sulfonyl]ethyl}-N,N-dimethylamine;2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[(1-{[2-(4-morpholinyl)ethyl]sulfonyl}-4-piperidinyl)oxy]-1,3,5-triazin-2-yl}-1H-benzimidazole;N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}-N-[3-(dimethylamino)propyl]-methanesulfonamide;N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}-N-[3-(4-morpholinyl)propyl]-methanesulfonamide;2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[2-(1-pyrrolidinyl)ethyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole;3-[2-({4-[4-[2-(Difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)ethyl]-8-oxa-3-azabicyclo[3.2.1]octane;2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(vinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole;N-[3-({2-(difluoromethyl)-1-[4-[4-(methylsulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazol-4-yl}oxy)propyl]-N,N-dimethylamine;4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-methyl-N-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine;2-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-methyl-N-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-4-pyrimidinamine;andN-[3-({2-(difluoromethyl)-1-[4-{[1-(methylsulfonyl)-4-piperidinyl]oxy}-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazol-4-yl}oxy)propyl]-N,N-dimethylamine;and enantiomers, mixtures of enantiomers, or mixtures of two or morediastereomers thereof; and pharmaceutically acceptable salts, andprodrugs thereof.
 30. A pharmaceutical composition comprising a compoundof claim 1, or an enantiomer, a mixture of enantiomers, or a mixture oftwo or more diastereomers thereof; or a pharmaceutically acceptablesalt, or prodrug thereof; and one or more pharmaceutically acceptablecarriers.
 31. The pharmaceutical composition of claim 30, furthercomprising a second therapeutic agent.
 32. The pharmaceuticalcomposition of claim 30, wherein the composition is formulated forsingle dose administration.
 33. The pharmaceutical composition of claim30, wherein the composition is formulated as oral, parenteral, orintravenous dosage form.
 34. The pharmaceutical composition of claim 33,wherein the oral dosage form is a tablet or capsule.
 35. A method forthe treatment or amelioration of one or more symptoms of a PI3K-mediateddisorder, disease, or condition in a subject, which comprisesadministering to the subject the compound of claim 1 effective toinhibit PI3K enzymatic activity.
 36. The method of claim 35 wherein thePI3K-mediated disorder, disease, or condition is cancer.
 37. The methodof claim 35, wherein the compound or the composition is administered incombination with a therapeutic agent.
 38. A method for inhibiting PI3Kenzymatic activity, comprising contacting a PI3K enzyme with thecompound of claim
 1. 39. The method of claim 35, wherein the PI3K is awild type.
 40. The method of claim 35, wherein the PI3K is a PI3Kmutant.
 41. The method of claim 39, wherein the PI3K is a Class I PI3K.42. The method of claim 41, wherein the PI3K is p110α.
 43. The method ofclaim 42, wherein the PI3K is a p110α mutant.
 44. The method of claim43, wherein the p110α mutant is R38H, K111N, N345K, C420R, P539R, E542K,E545A, E545G, E545K, Q546K, Q546P, I800L, T1025S, M1043I, H1047L,H1047R, or H1047Y.
 45. The compound of claim 2, having the structure ofFormula Ia, wherein: R¹ is independently hydrogen, methoxy, ordimethylaminopropoxy; R² is independently hydrogen or amino; R³ and R⁴are hydrogen; or R³ and R⁴ are linked together to form ethylene; R⁵ isindependently methyl, ethenyl, dimethylaminomethyl, dimethylaminoethyl,or dimethylaminopropyl; R⁶ is difluoromethyl; Q is phenylene, optionallysubstituted with one or more substituents; T¹ is independently a bond,—O—, or —NR⁸—; T² is independently a bond or —NR⁸—, with the provisothat the atom that is attached to —SO₂R⁵ is nitrogen; each R⁸ isindependently hydrogen or methyl; and X, Y, and Z are each independentlya nitrogen atom or CH, with the proviso that at least two of X, Y, and Zare nitrogen atoms.
 46. The compound of claim 45, wherein Q is1,4-phenylene.
 47. The compound of claim 45, wherein T¹ is a bond. 48.The compound of claim 45, wherein T² is —NH—.
 49. The compound of claim1, wherein the compound isN-{4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]phenyl}-2-(dimethylamino)ethanesulfonamide.50. The compound of claim 1, wherein the compound isN-{-4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]phenyl}-2-(dimethylamino)-N-methylethanesulfonamide.51. The compound of claim 1, wherein the compound is2-(difluoromethyl)-4-methoxy-1-[4-{4-[(4-methyl-1-piperazinyl)sulfonyl]phenyl}-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole.